Understanding Immunity By Tracing Thymocyte Development
Understanding Immunity By Tracing Thymocyte Development
Understanding Immunity By Tracing Thymocyte Development
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
Appendix I: 50 Sets of 400 Randomly Generated Tri-Peptides<br />
1. mdn yqf ntg hyy nhm ctq nff ege svs cef smi vhn syy tsq tps ink tlq tng nlv kgl aqc nqq<br />
rqy gsa ccw fsg grg lww vgs qll fmv tyy wdg iss slk ppr tgs eds yck tpw kws ift afc vay<br />
tvm syk fkd icf itv ytk trl knp qyr apd vqh flq gdr nqc vff rsy rre fat sfk gqt cpp ldr akm<br />
dpk afh pim scs ael thi vsg trv vke nmi ryf dft tkv pas lyi rev hqe gwa nwt nfa npe chn ifa<br />
scg sih iyp qhe mnq qtl reh akt wnn nyr dmk lmn drm hna wsm kle qaq egw rtg hqt kkk<br />
cip mfr qmi mdk tam drp mmr mry rwi pel hqr tlt ekf amv hlq eni tkc tdw vta ygr cts asp<br />
amp ahn hqt rrq dsh adn vfp fvc int ips cyn yhv gle vra cse afq eqh gha yfq fwc sgq ier<br />
gma glw ynv hva ehf mtf mee pvl gdi eqc aif gni ivg whr qsw mst hnh dcq ekm hmy pay<br />
mpp ege kwd ive stv thn pct dkr hqm mve lgk lyy leq mwn kry hiy tcd dss sii dfc adr rcn<br />
wnn ync gig fty gda pnq miw vce vly cnd kdi dqk qgl nse fep plc ahs wkw gfk tdn ntq<br />
mtq nis edn nrp gsd icd aes hgt fdm ggg dmd ytw qhf qee qdc ade ftv gil fqq asf avf rec<br />
vpc nww vih mey ery epq wcs ekl dlh iip rws avm kiq mpi lws sgs cqn whc dlr asp cpq<br />
lys nsa hly kef itn ent cls ikh gwh mpe gwy mwl agy waa cwe mwh gic ykq knw mmi<br />
qmk atd ynq pdt cpm eir qqd rnw fcn iye tgw nal yqd tla eck ady knw hat pfk glf ipy nfk<br />
qfg yai ldq fgd nqr rsg iye ede tcg pni yil dgm nvh yav fwg yfw dim akh gnt wwv dwm<br />
vdd pdr pvv gpa myi wmy grn lee snm hal syl tsd aiv irp hhf dth dwe mfm fec mym mii<br />
hgp lyl vwt kag rey vpw tww aie ggg mfa dad pee epm inl qrh dvd pyp dpd wva pqa pft<br />
egc elt qld mwk flf tfg qff hci avv eql gmw dgn edw vpa tfa vvp pav fcf vkm nls age vnt<br />
ymq pqa gek yfd ked hkq lhp isl kpn ckl ppl<br />
2. yfe mky ykt qme hsw ead hrh lys kaq qed fsm kme qnd twp rec lir tkg wfe swt nml<br />
ams nwe arm kca ccd yif aik twh mhv pmi few afp fne kep sqa fmt lpy rwh nyy npa lnr<br />
gil khw ahs ykc avl lkh qan hks lmg nvi hev ydg anv pct wys fte yqh sfn mhc nei wdl cin<br />
siq dkw nwr qqa sgv dsd lsm amp agk eww skl ccp war kmk cgi fiv elc cyg iep yen lei<br />
ash clq yfp ewt tfa nlg mkv ciw mpa yci mtk ylv avt adi apq rpg nla dsl wgv ydn drl svr<br />
rkt ttm knk rrg yrq kkt adv qkg vfr qka plh dmk kls hvc akn ptk iks cll lna chi fpw ekc<br />
pnv vst csc dkf chs pfy nvn spf fkl drk wsd sta yte ndc mgd nyp cwd svm kyd ssy eng<br />
wsk clk rps qpg nyq fra nit efq wph rhs ldd ftv gsv qsr fsn swy ywt qvk wap ltg nms amg<br />
ptc tkm qmi wmh pww lkm adr gds stl qfh lnt wen yci qhk fkt pka gfi hme hft sml iyc<br />
ede gvn svg wef rtt tdk wrs fhn nve qnk yeq ntk glk ksh ewq dsd hym idw ire nyv yee vif<br />
twc mgg wsg gaf iws afm hnq lln fsp kwn ggs csm ets nsg vvh tlp vvv mwg sss eyi gqs<br />
ytp mdm iif hyy dkt nvw wgh yac ewa vqr qay khc vcc vlg ycl hqr kew pcy ems emw ftc<br />
cmn amk kec pnm iqi mcr mvv wmh dwc mgy fsy gpv ffs wcw wek qfl trm gfl qty wkn<br />
lnq dpq hrr vhr ggq ipa dlp hgi dns tpk rgl qmc vlh tmi fky npv dcr dks teh pvc ncm vrr<br />
mct slw mid kwk yag ldd lse stm fpf nha rpm wrv pld raa edm fhc wcl eli nhl egy alv fmh<br />
vsh sqm nih ykf mnr ggp elw ewt wrp nhd nif yvh phs ytp yse qts lfs ynd cmm wcp waf<br />
tfr ily img kvd etr myv rhy egv gvv ede iit arn yvr ipf wsg sdi nig cda kie dkt gqe vme<br />
dhe eal rde ssk rfi qia dgd mii fyg kfr mac pml whw kve gtt fpk icf hrh ter tar cww npk<br />
asl glp wns mci gkv wqa ham wes shi qel peg qyl yhm ltn vqi
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
3. qcd klm nnl hyi nhc ksr rtp prn gid ynk gst fkg cla ytm drd mif wti ief ywr yrl mnn qce<br />
cvt yqm isr csf tfw eaw mwe rta drd kac lyp tcy yih wsy anv fek gyl cpf hve tgd kld wfk<br />
kig irl tng ert lsd ici ddd wvp kws cms mpr dtn ehn fff esp qps sfr cef qlc sck swm wgy<br />
dld sfa ngl rdr qrm lfm lkn hcc ipe tcf hqv isd hcg rwi dcp wgc hgl ccy wqy qrf mks ntp<br />
ghm iff hra der llc vla mwt iem gnp mwr enp lwg irc fpr vti qtc yyk qhc lyl dpk alq hhi<br />
pvq nqi imv cwi tvk htc tcv ifs vkd idh hgk tna qcr gky ldw nkt dvg mfq vwa ttc tly epv<br />
mck thr fva cgr qte nrd kny frs rdq yps csd chq qfe kvs nfm rah paa str nfp mcn gds vch<br />
lfa qcg hte sni hph dll lts yyl ncv afn mqc dhk gik wra kty aye idk qfr shi yqc yqa nhf<br />
dym vhl vvf kwa tmr ssf nev ycf nhh mrm isf efp wte vwr erp mcy rch lrv mrm mdi awq<br />
tvv vnw qmn tqy lfa lel erk igw lpw inm tym ydq gfc ptk yvl hrt nvp kff ikv nsm plm crs<br />
iam tvv nie tpq rlf crt smg phv pwc hqh rev wyg wpc laf kty ngw fdf pvs phk vcc rdn wac<br />
ham pwc wtw krc cla liw yhp spm yqf nev fmd nsk fpf dpl fvk wmc qms gvf ngi dhf lve<br />
eyw lrd yrv hmc wmg wpg fps ppk mfc vys nid fkq drv rfp spy hdk pig khv pyp vha asa<br />
htw ale yvh mhg twk iil lkl evq fwi keg fvq tsa mig wyh emr ppd tmr aed fsl nmp ytm<br />
gce eiv avt sac lcr hve wfd tla vhy tsf nsn tdp ggk cys ini lls epf pia mpl sfg ldw gra mki<br />
lpt vnr gsf iyi aht qnr vml rwr idn hya cch nfh fnw qed iqr wgm pnk kdm awe nyf syd<br />
kch agw hra dak mvm wik hag emk yws dpk fef snw dfe pcc mvn snq vqr wfq qcl rqy<br />
gec tli mvw ccq qdy cip yqp rfk cwd vtp ske wrl cdw wnc aqf wet rqy dnq mce wyt krt<br />
mfc hkm mpd caf vac lti hit edd fps qhk ncd<br />
4. hqk kmk ksv cgn hcp lly ccf vti lqk hcm lqv ilt nwy hnp ghl epf tph gec ppt yel anm<br />
cwc ssm gfs lmg lwn arg crf vyf ftm gaf yiv wyp qwc nfc eka wid lav yrn vsl ald ssf qgt<br />
wav tsm yvf kwm eya efk iih aei cid myq ywq rer eyc iey lwn dnl hvq yca vfk qts rkv iec<br />
nan mwe rqr lft ahq cvc mwr qcm snr gri gly tvt ymg ylr kps dcl clr fki ypm frp pkd lqi<br />
anp rhl nmn wlh iet mvm qgl lep dfq nqa gte nlh cnd gqt qth rif wtp gmw cyh fqk qkt cvn<br />
elk rqt hwh hac vvq pyf wth kgq rhp ers yig qtm ttn nlh npd vqy yvy ieq ahw dtq tnp tyy<br />
vnp pfk ire wic nif wfy yfn cdg let gqv ssa kmp iaq qtm klc clv fvn phg gym qka kgt vsy<br />
ivl hwp kdm pmw lva ftl ney iag eqm kee qei vse aem inw fed dea sfw qwk ynq iap gci<br />
kvn vfa fng ipg tkm ive qde mee tcn kdi sll nea gqp kmv psa ksv slg mcy atq nwd rfg yvr<br />
gli pph sht mhh tiy eyr tfr vnd nmt ktr qvh heh vqc knl qwl clr lag mtg fpl hhp pds tgw sfr<br />
tkf vca hcf psg vmy rcf wyy tld rnw can mww vda vty maa wck kpd mcf rsh vsh syf dwp<br />
mhg gkr pvk lcw fwd nqr hmi rml lyc giv wdh pga dpw qyk qvd knc gyi ypy pmr vce tsr<br />
rat ylk haw mdq ymf pld clp rsc dqg kgc dek vmm dsn hyy nfk lfg nce asy crk svp fay<br />
ymn ghm wwq ddi yrq wse rpr ldp fwv vcn sdg wpf kyl ysn pwq imw ylp aqg fel sgq aay<br />
iei wva slm rkl fhl vli tmc hew hdd mcn kvn yhd vcy sdm ytl hmv gqg lpv ppe pll psp<br />
eim wth srf fdv vhh wfi ivn lek ehs atr gpm fte mhv thl vyp wiw evw syl ctm kvf ayy ysn<br />
rwg ivv lle tkl fqg tdi siy ngw sem nnd qsk aii kff ydq daw qwk dfd ggh maa ges ifp fcm<br />
vmm tvc esw qcy fek tdg ypv qmf erh skn nwp aap qfn tsp lel trp mfh ieq ylg vya pmp<br />
dhi iiq npt dsm ykf vtg msl shh fca cqf vem
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
5. iwm mvg yte lfm ehs fit kfw thc fmd vnn kyv pwr ciq hyl dkm tgm rtl cvr rkc laa cpd<br />
fkg smv kfv spn wah mls dlw vvn shv liq gfn rwp enc gss wcc dth lki svd ahk iel wpf grg<br />
hhs ilv eey aqv mnf yvm nge fle eqw ptv rhn sqs iqr rpi pet cpi frk alt nnk dpf yhf wkr<br />
nfv ehf mct pgt laf kvt cny amp tep vdq awv gtt asi pfh dde nqi vyi afq she rrv cpf qrr<br />
emm ygd tlc ldl hav clw swp gsc gvt gah tpn pvn adv ahr lpl kdn edk lgp yac ltw fcs vpq<br />
cke hcm pnv hwe vai ptf dnc vsk feq mhr cgh afi aan sdn irh kna vdp yqi wdi tkn egk<br />
kmd gwy tfn qyr ndi dff akd nhw fki cwc csm lff tav vlc asc qtm hyp hdf pqp pdt ehn fsf<br />
igy vww fsw gye kqq nfw lnk nge yca ldy nka vvf gwa yma eyt fil ksv fgk qkt dff fvw rcl<br />
fvi qtr hhp fgy wsw qld qda ieh lds hqv ipm cyd yyh mrw iag ece dkw cvc iet qqq sdv asl<br />
ygs pvc cff hlh cnv amg lld taw sth ekc sfv ggv mrv frp yie yvd vfr nqt raf thm ggv twe<br />
fmr edi wkr nrd mnn trr wfi lqk mky mwn mes vqy avs ctn pnp mqn air lww alk ycw fwr<br />
taw iga red fdh cii hpw lww him qqp iyg agf qqh tde ted ngd rrd yek pya dvn ssv ecp cmv<br />
tre gcd wgs sgs rys yqk dqw eyc pey pra vve qfw aiy isv mwn rcv lmy myh cch lty lna<br />
skf fah mps awn ghg sne amk ptw srt pyw ggg kve lcw hmy fne hki eli qvg ddh qth wcn<br />
fll saf svq hvq lds pqt qvy evm cdh qgw nyd pdq tdh ree qch iqg fwy inr ykw dat gft hld<br />
vmh kih hmt ihw wyw ega yyh mik nce ypp kky idh ltl rmr err fpv ymw npl tqc gsv klc<br />
gvr yeg irm mrl kdp tgs tah wgm hka svc cti tsp cwt yvc dgv knp fwd psr ics ert qsn lkq<br />
ntq shp gmy gav tgv tqt dpi dla ndq yfc lsp ssf cdn glv nmw igh dem wgn asl yey atq rdv<br />
din pki emf psc vgs msc wkv ene nme apa<br />
6. niq naw syc qmy cmn hea cig qfg aem akw fyi npf tsv lsp aia pcg rqm arn apq emy ffq<br />
pma gni kka yyt avy yfy mgy lwp htd net iyv alq nal ysy iyf sfy lwe lty adk rmc vrw ypm<br />
prs vnp mgi eit mgl kln sqc fra eha glv qrv vnn atf knf psm hkk vht vrw fmg ets eiq cel<br />
scw gpt dlh pna pdi vfp ayk gdw cdn lav ksd prn kas qkv yvy ats gnv rwg ntl rfs red mqc<br />
mpq hri aqe kys hdn rsn scw vwk wqp rdk iwv shh hhn aqe veq ncf mte hyd nyc wpi ddq<br />
amm aqe yeh imk wkv mfq hyr rna aca yrn pif tcs sll pvr ecc gre dfi gql ami wmf rns dyt<br />
iiw wnq siy pyw yan yqi ami hli avy cde ksh fkp gap evt lam cpq aec pqm vgg vte wac<br />
ywk iky esn evd cps hle rns ryi seg cvm icm dys tid nkp pgl enc kcg val cmq frp naf ptf<br />
niq evi pry pav pdr kpf khr ghw kyg the mvr htd nki yel rhm whc mke fgt crn igr fgh wyh<br />
nvt kqm paq ykr fdl dkl aes hat fkf dvy cai tmf nts cct vrg pfp hni whr pfc yhq ahv vas iai<br />
ntm wvd rmv gwd dmy cap lip its qyt pvf fgy gii nqs vin iwc kwi vrr kpc mqa rmg avg<br />
afe dpt tmf ccc qnr crg svp lsy fvi aep aai pmv sed err alh rmq cgl pcp npl enc wth ngl<br />
qqv wvg yka rem tfv yyf lnv lnr gcs qly hgl vle rqq ppy gda pnt vwr lgr rgt cmt pip tye<br />
tfm lca eqy ycl cfp ers evh ely shy vgv rvm gyq ldp sct tqn vrs pgg kgy kcv vvr pyi emq<br />
fli vyp lnk cqn ihs mes rlr qmy qgy lyy aic rfh deq ety dwn vqm vfk vfg ypv tcc mmm<br />
eak ypa khf qwy npl cty kat eyf fpy tsw qnf kyt tvn hhs fpf yhf iat sah qdh pny hwl dwr<br />
vne vdl hda dfr rfi afg rik mds cce emy twq fkn ept rte knr grv rlq scn eec mtg sdq ivg cac<br />
ikk lnf fwv ftp wia vlk gkd yhf gcm yks nwt hqe rwc qet lnr ngt etw nma vik lae qnq vsg<br />
qhh lgv mdc ehp wey sse ayd
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
7. wnt wqr qkh cyl ilm gmp yhk gyh vte cay qta she tkq dei lhm yed pgt ynq enq wns idq<br />
kdi ith psc wig wgc qwg tcr kne dtw pgc khp lfg dfh qnp mkg pdg qlr ykd gaa vwn val<br />
fdc lvk wwy mys qyy prg dad asl yvr lde qks gly idh drt ipi vpi waq rar fgl qfw nkm nqm<br />
pdi wmk yiv rfv wfm egk ata crk twe kir ryi rah nct qli daf wcf vhq rkg yaq lag tph rdr fit<br />
qty mly vsh waq sch iei dmp ktl ksc kts fiq rve alq lvn cae nkm kkm pal kwe rcq krc gfr<br />
gcd hhr vay mer llp kng evh tqi eqv nsa kei lvq qwf nrc pla drm slt ivm qgc qwq mil igy<br />
rwp rfd rpl kcm tyf rwn lwc mla ane lhm aih rrw yai dlm vnc hng ccv ysc icm aia kyn eav<br />
rkq dqs eci qls mpw imv rdy ahf dlh hrh lan qkn eqf vtr cfr wlc kdl imf awl imq dkg yya<br />
mlv yye frn knq vct vhi klf hvs wcm aaw ydq lqm par hha cia pie yvg fek nar chs qma iay<br />
rpy hch alc ihy prr mtm amp tih mym fhc wsd wty pkm efa ngd myg sgr hdg qsi pem fmf<br />
hpy ykk rfl dwg rkg adf ayt vii tsn wfk mtp lhv ava qfa hgk ter ths knq tid err hki sai qfr<br />
cgv ytv viv pvd mrw wrs mna nvq lnc maw myi qkp fyy spg vqe wem mlv pgy prf drw<br />
aak tsl egp efq gvf sqg gnv kyp ykw qep kpa vdd lpv ecq rsq wkf aft ivn gfd fff rgv afa<br />
iys cli lkh nsy yek mwi stf elp wwv gtl wrm lnc kwh wrl nsw tms inn sfg ghd mvh win<br />
kam dqs tay phc swp drp ady tnh yhw vna whq fgs ysf hvc idd hki ras dki lqr qrc rkk kgl<br />
str prn emq phw eph phm ref hgp fra iqy spd yny akv mqm mwa rql ety pcv sie hqe qpn<br />
vkk kdq tgp fqy fsd pcr sww vhv mmc ngm vwl ame yvs hwh wgl gal svm etm gka ggi<br />
gec nvg fya enq yyh efl ski shg acw erm apc cnr tfe csm keg ief nrh rny pde add rqg lst<br />
dnh afs ldp lgk qnc qnp afr sdl ain qqm qnd<br />
8. hmn vtd ikf cni qek fgq pyt ani nas pgp tgh kms hnt kva dpk ehd gdc pqk dcq pll wrh<br />
raq rev ymf nnv ihw eve dhm het ade tks iit knh afk nwk mhi nvl iit pmy tpw ikf dcq wlk<br />
rgn csw hcd klm ddr liw snq ehe glw frq cav ics qcy efv ewn sws ndt wpl rpy tre lfg ryv<br />
tlk dht atw nmq fgr gty hpk hqf nym ckp kwg kms mmv itf svw ctn wif cle iah dkt ftw<br />
kre nyy raw vhq mei hhk hwi kkk mwc lqf dew pmg pla yqq cnt wwg pfc tih arl ipk pec<br />
shf edf pmk rhs iiv dte pet gma iyp yhc rik ykp wln miv yrl nqn scn wlv kyl wii sii wif<br />
tkp miv kri ffc mgg khe itf iqg wnk mkn lfc rig yyi mts tpa iem rvl wks fnv aca vrv awn<br />
kgp agq vvq iwy qtm mcm mar pqm ney hyp grc wkv hts dds ein hyy kpf ekw cmi qfc<br />
ema mgm nma kqe daf wif tmh hgq nkw egy kwr ftl gft ymt thy taw emc pwy ckm hkm<br />
sqt ftm gsp fsq iee ycv ncf qsv cik ems hfk gse frh des hra fgf ank mle sty cqk mdc lmd<br />
nny lnq dyp glv wpy vqy lnm ysl pse aih gke pwa fil kgq diy ime pet wkk wrc rpy lrn cnq<br />
eea mms csg enq lmg gsq ptm rqe evi erq kte kyy gwl kgi wkf thl svm cfd acq vft yfr ccl<br />
dqh mlc vlf ckc rsp lkn pfr gsc tte tra hkk qhr tae gvy dqh idr lie led qlh yqh vac pvd tqk<br />
nty vai mmi hwq dty phe rks hwm hpy snn syw err pep fwm kpc fka tnt mrv tgk ysd lkk<br />
dkm pgk hvw rlg fwv rhh cai kpp stk cnm hfs dps sif ely ihe itr qsf elk sda sia fyf wak<br />
nvv fqe kcf edv nlf ifd asq ten gwk rvg aee wat tew yhn ayk ckc ena swv rgk hrr iqf rfr<br />
wvk tnm trm yhd scw lgd gnw skl kaf gkp gfm ghs eky evr nkv ggd trs yif lmh min mwn<br />
rmd wsv vrh yyr kdh hvd smh ivv qwe fqw akp iwq mvv qcy hqm mir wst tqg rah yrg ylg<br />
pic tpa hiy sgl tee sqe sks yrs fma vdf cdy crh seq
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
9. mdq wvc pse wld kiq arf ces fim pwk fvs aym tcc wil qgq igs ipe dkf mnh let ymw lpt<br />
wki yke ifp niw cgf qni vrn lir rgi nhi ewl fyq awi par itn swq vec dai yag rrt cpr yfd sky<br />
fqn sta hyn eim pet akh efd kcf fwv cqs gml ymi lve pqh dae rif ccn cns aep tce ilk fcs tlk<br />
rgt vmi wpe rni hpw gge klh aha vek rfk wwy cfd mmn iqg idc pye hdf evt ers nka mqe<br />
agr gpt gfp cyy qyg edh qhp rmn lhn rdk ita tkd tyn fcd lve csr mwg ewq chm arc iam yvl<br />
lsv hys iwf qnt eid dem qke yes vsp kar anl hdg gcg iqs fnq iie ynm fwq dgv etr pwe fmi<br />
awv qyf wfn rhw lad nie yyf ktf vyh fpd nlp ynn adt vym viy rva mkh hvh sqq eef hyf yrc<br />
gvc akl ydf ccs lqp agi ppg ggd qan nty nkg wpv vnn clv qhy crp eke wyw hlf scq tri fgt<br />
fqk cfy gar qpt eig geg cly fmm cqt dhl pqt yna gwn hgf ekc yld lmd fee wgk wrm qwh<br />
ysr pii amd iss mls dma pia syg yev ema kni rdy lva pnv vfk eyv pih eaq sal psw yqn msd<br />
faq vfn rad rhf giv hsp twm pfm snd gil inl grt ifc ndf tqh wdc tda kpy lhd mve few yvi<br />
sen ptq nmq clf spl end dvf wtv rev ywi mfm tkf rsn ehy qfp qdt pve mrr mqt iga hgs thd<br />
mhp cag nhi maa lcd mec rpm swd mls tci ypc cgg ekh iry tah aqh yrf ydh fkc afk kdd rpl<br />
hhv gan vsf vvn npk wnw yal rhr gni rss fwd rhw wft ari grn gph ntp yfn hms hev ymm<br />
rdy vyy ees yqi phd pvc fcr lpn qew kmh fdv fyq yrf wdk rrn dwg nvd ntf qym nnd vdq<br />
mms nsp tiw cki yrm wrd whe dmk ava nnf vqr ndk qlp akn lsq vit hch dka lin cnq aiy<br />
sdh flw ffw pqp llt isn sas ywe fqk iey idr krr dri wvg yfl qan vvm tvi vhw ccr dak tch<br />
mhf mid lhe epm mfq mmt dny sic ctw aya lkp wnh pqn khi kwp qqw tsw tfq sgi nre isi<br />
rpi chn qqk ays gyv hgq nci qqw eee<br />
10. gpa qcd neq sse eht wws lgg dpl dys anr frh pwn rgm gsq tpl swd dic tsm qwy lgr sgc<br />
lcr twv nvd rnc fwr tgq mya hca lit efw nrc qeh kfw lfn gns hly ipt tme waw qsw qin hqi<br />
yfs kla rwc fsp ryt cck gkv snw peq fvy aft qmp vge ser dlq qgf ycv yis nyp cah rqe mya<br />
dtm tec pvp tff lmc egh wlt vmm sqs spn vyf wsv qnd qsa cgm qpy kfi ewd cpm rep tmg<br />
sye rci pgf hyv cnl ilr nfq fnt gkn dwk rpy ysf pas lts tfq sms fqr gge nkc nmg dwq ppa<br />
emm cqr rtq nfl tgq nwi icm epp nfi hfs rcr qmh agg hkl gei mtn qma cil qhp wrs pqh kkd<br />
qmw ple ehh dnt mhp gel fik vwr dcm llm iep vis mlv vvt agm snv npt eqe tpc idv hfq nal<br />
seq fkd nci gkk ndf ggl dtf dlr ild egk fry yqn eqp mpc hnm gsy qsn wrv pps nfv arc nkl<br />
pcg gcn hlv twp mgl wqt tnn iny emr qmd pyw rcr drw nes qcv lqk wdv sqy lhh kna kdn<br />
cck kyg qas giv thr skw isi rdg ned rli cla aff hpm trl tit rkd yfg ciq hkm vfd idd mnk ewr<br />
tll yap tve plt tri smh fih tcp nwe sdt qwp dcr iwn irq cpc rmh crc aqc kis tfr nfa naw efy<br />
rnd qva igp qvg rtg mvv wqp gsd pae vpd hmd hfw wdl yec qvl ftq ppw gfm sgm aqm lsy<br />
deg awm lea pik rlm aiw kwi iti cst laf lai isl htd flh waq rsp iaw mli hkd hel kah fcc wsa<br />
tmm vnc wsa ygd fah sah ins clq wkw scd kes vrs wnt qfa sfr isy hrw yrm sfy fgn hqi<br />
qwq hsv lsc qgt yyd fid ekw pai wag weq vek hhy ctt yae tek emt ste fcd mvq kih lfa pwr<br />
ftc fmp ikv egs gyq ewe acw iin mgg das npd iih qhe mqe shf ynw psd kpl ryv eam vha<br />
vli vcy mki hsa ncw tsk kyc ikg nmi hrr cem clc vkd slk ena cnw dcp dmf svl ilp pkh ekl<br />
fia caw gsn are aiw vdm hhi vel gsy lth can ssk qld lql fiy vqm kea hgl iie wne sye prn<br />
igm fyn itr dqg myf mhq ads
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
11. gpw ikh vse fat hgr pnv qlr nfq swl wfm fhn ryc wlh yyv tyt cai ayi ygn mcn atf pkc<br />
tlv eiv dtk stm pic aty fck nsy pqv aia myg kgn ire vde siq npf tpi nil tiv hhp rtn pqq tps<br />
dyn kki aef ycp mhs yid lne cma ier iev hwv gnm ike hhv qgg haa ktt lrl rfc eyt ste plw<br />
rma dqp whh nef mas wpm tfv vcq gac wnd egi pwl tar ewc rgg iqn cyt ngc rst ntw agy<br />
lka nsm qrh kqh aly tgk das vmd gtc wrd sff kmw hgk gac kfq ncg mar vkg keg lrg ndv<br />
tff hrc lyd gws rks vnl wlr asg sql tgs sny whl mse mlf ded cgl meg ynm nmi tec cem edt<br />
emd slw gph pta dan hei wsg vyy vcy fgm sin wgl qva wma hca ris var yym lnd vvm rhn<br />
vca ham yti rcw sln dre lvf arf cme ind lge epp arq fck att www tlr vnc nlv hqg mpq avy<br />
lhk aqy kfc vtk ivy krf smf nvc src nfa shn rht its knm cgk gfp sin qnh var igk qet thh acy<br />
sln hsn ydy ryn gfh hvq qtt cma can vgg ers ptp sas die anh ngk vgq qfa isy eps hgl yhk<br />
cyv dkh sde yiv tlv tdc cft rlm gcg vff sgf cla ryv rif wss mhq csa rgq mye iwk ygp mpf<br />
sld cgn chp hwq dqs vwe nil yin hhr ken rrg wmi rne nri trd pqw vfi ken ecd hgd aae sek<br />
mdt khe qvk ieh tcf fvh gaf pqs wtp eee egv fie gmd rdh vtm rsd fha gwa ppf akd vye aph<br />
snq eed cee ylm leg qvr cka nel qra mav kfr vvd fgp qwc kat yis yya fnl vpy dla epm prw<br />
rmw gvp ett gwl ngc lst fvl mnv was crf ekk mpq yll ldn hfg ctc pid yyd dpf qci vik rqd<br />
mnm amw ifw ilt qvk iwr fcn vfh wgt ted gff ptw ney chm sev msp rps ttl ewn gme ecf<br />
err tyy qki dcs pry dfc inl grl cpm yts tdl wtr kla vqr wih laq vyt hat gga cqv ecn ykk ytf<br />
erh fgv wlw cnr vlm rgm qva pkg dqk ryn has npe csq ych egk tva vny lec qav faq eic lwt<br />
raa vry gad qvt shr eme<br />
12. leg sre pla gcp afa pts hwd qqm sht wpc mdl nvt ran rgc rkp tml fcs nsp trh pri sml<br />
mky mrd wqy wmk sri mqw hqk pwq pmq ach elk llt day pmy qis gcp shs sqm khr cve<br />
lwq ied ahq yig wgq reh npy ecg gai ddf ged wqe dpn lsh dct tpl ndr fpl evs kpf haf rds<br />
eiv tpg sha lkc mhg mvk qdi mgq isg yrk lyi gfw hqk dea tre hyd nyn dgg ihh eed itm alf<br />
vrm pnp acl ldd ptd wya lwn dil wmp pre evm sme pes new pwv snv gyl amd vky tsg hlg<br />
cic hrr lmg hqq vlc egm khr wlh kvv acs pil ksq pdp cdc mly srv sle tiq fql pvk gdg shc<br />
rap ppy sfi psh rtq pes fhc srt mpi mmw tqv mik vyd tqf qrv ied vif dkr ske ids wle gis<br />
dvc vqh nnl pkc cng iwh new trg wnq vck pdk tfh qgf mrp mnr vln gag phl yhy qfm qqm<br />
smn qkh nld sph vri yqy drs hrh iqn myf dtr pcl tfm tne mmq tpm tvm yhm fst egd hfr vlv<br />
cre wrk les hge kae nqg hpq lyr ang fkg sqm wpf lst wrn vfk cyv qac das mdv qgq crs fnt<br />
hvn alk tfm rkc yky gak qgd krq pnr afs vls gth mgd ald mdl spd pft ina nvy kwi hnd nyf<br />
ahq tnq tlh gtv wat fmi gfy vrh rmr hee kcf rsw vle tfp cfc eke idi spr dqd lac tyf mnr tdy<br />
vnh eia kas rgk mqn evq nnk dha fcm mfa mmy wgh dig tnm rph csh ykv kvd dvn hhq<br />
vwm ehf ipn kqs ekg vhl gvq smd ild plv kck mat kkc wsg cyd cqr yht tki avg ygc gcl hsg<br />
cka gfl nqi wnf mfw ghr att lnr wyd gfq gvt lpg pgy acs wry mpr mft asv ffe qkr acn ewy<br />
wii mfi vlg kpm qqi dpg cwq ykr ade tve amw ten rsq wem gtp rse ppe mlr qpq ayf tqe ifr<br />
ylq hqv eqa ccv gii yew sww ppf mhh ilq irr cwf cml aic nit gfk wwk chy tvn vrm psg<br />
ncv rmp csn yal yrp yfq qpi ris veh vgi kgr wsk rvl wfg gsp cyi haf rnt ifp cse vtk pfa sai<br />
mve grn gkv rav dyw viq fty asy qmw hqk
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
13. fvm wsr mmk lhr fqa qwk lam gdn lem sec iqa lyt mpe yrv ddr dpf yah ppp ilh slg<br />
qcw nqy nsa hrv twh stn sgm kmf hes pgr plw mcc vpd qme lgg vhi dnl erg rnp tlw pth<br />
grm laf tnp hge std lpt gir acs enc dgk maw aek ypw vfe fcd qcv gye wkg prq req ytt hip<br />
arl haa hpf yrd vnm fqc tgv tsd hws qsf ctw arl lrt aga qew aqh afd ned tln wkn yke chy<br />
vpk kgv qkr hkw cml ege rdw rsw aha tmh snh wvy pac dkc hva yqt wma cah hnw dpm<br />
dql vti mpk pkc klm eei ywl wwk wdy wlc wac fde nhm ltd ymy vws een hky vgp vfs<br />
yge mwl crs clw dat kqf led qac scc wtm cvr cci vnk mlr alp ckt crk mfk hya eva hfk nle<br />
dmy nqn nde yqe hvy gqk hcn ltf tns tid ilg fnw nyy hwq yev mnv std hnd psv rdl fiy rfy<br />
hgf rta waa ycd qvp gis wic dmd lwk ppp ycw dwi kmh yfs pky fiv mmt vsv vha vgr kpn<br />
pcv vdy fnt qcq hdd wvi krs vvn hfs lcf ara men pid iek drp qev nik ksk rat kcn gvv qnl<br />
qgk isc ffa srd edg vme eit kdf viq prl rvt laa rnt wam cmy ehh ish kew nrs ttm ily emf tyr<br />
vql ykc vds fng mwq mmm mie dkv hcm fsm hly qri vkp qwf nis prq cma weg frf lhc tri<br />
rmf any pgh pdd feq qcl qms cnh kss lme gkp iyf hwh rcy vvy phm fpe wsh dky fri qnl<br />
pfs isg ikl iga hfe diq nre iaq lvr ilf hal ksn nrd rai clr hmr cgl wge klt vve lwy vsf ike lvk<br />
fca hdk ntc scg mkl wkk kwe awr mrm pqt wlq hsl rfk tft fgv spt hfd vpn egg itm sni qdq<br />
pnq qmt cmn pgi yav adg gsv cfk mpa rrq dcs qcs dlq ici sdv ddf pdl rkn sed spv pee pcc<br />
amm mdq iid svg hki pse vtg qiw wrk cll rtp cms qiy kap nei dpe dgw ygg hvw sid riy<br />
wdh frc akd iig ytg min aqh dfq agi ate igm wss pty aqm mcl qsl dns pli glh haa rtw hed<br />
gav rvs qwe ymc dfh ntp qnd emv nat lcf grm myy<br />
14. dyk taw gwt hgf fvv kmq vhc hmi hfa lnn dvt rgn ird dnv cnf rme mqq nwk yel tsn<br />
pfs mgd spt msq lmy spr icg trp ssl twd mee nal tkd emc kdp phk igc hfp mtf pry fpg ild<br />
qci wcv mmv myn vfl mld qdq vvi ifc lka fel det ptp hcm ivc mli ycy twh qnf kki qtf ehy<br />
cwi mdg pcw mhs qvg vsr scm yrn swp rrd lvl ndg hnq qir dsw rkh hml hvt tns yyr nyf<br />
qik efy yer cie hfr vgf pli hkg vdv gif rvy dfw las ltp sfi aph lfe wdm kqv ded way hhe nlt<br />
ykr cff rfy hnr gpe pyd pkn hmt pfs adl awk efs att icd fne fcv gdr wvk yca hwh tfg hay<br />
smc wgk whk mnk yei gke ain fva pfy evv ctm rkn smy fnn hhk mda ech gmw fwm fip<br />
mgk rhr ilh aal ifl lvi enw knk ayt shk lih gww rpw afr nhr ltd ceg rae peh hvm nfv yfq<br />
ddc swd neg ded yac sqs dsq dca rwf ayf gqg hry hhc chi kwh dyk skr vli hep skl fti cka<br />
epl lgf fww lcl nsn tqr ekq kmw nsa nrq imm kph wqa cie nyq lyl gtv lif hsh vgp kiv tas<br />
grw qtp deg ehp aha cqd ati pey ite hwy rli alq slk clh val nhh vlm cvy rcq agq cvp sgm<br />
ril ikr dgy pgf qpf rkl pii dvt dlw msf qlt aar knc iwm kki kry lrq wdd fqp qfq hgm dew<br />
grm dte hyt pgy nfv nky ytl wwy npr rgp mpl ekl tdk pkq csm dfg agd csm kgy sws yck<br />
csp idv mwi nha fwy ptf fnt lds kad dhc tkf idi fas rwd vfm ryf eil vss ecq acr wyc kas cyf<br />
hwy ivn dnk hqr vkf hnn hyn aqd pif qhp lya pfd hni chm hwr ksi lrt ffd rqs kek tqq wse<br />
tsh feg agd akq ydm lni vre wpn dfw qqk vvy spv fff dcy sms skk pwc sfk ahq cvg skv<br />
gtg wwi agm fkt mrm aey scr pqg mme qdw qeh cqc str cpm ine ywr cyv ept hsk ifd cgp<br />
idq tnd wqe hdr wky hak yem rva tmp rhi nil pty mnm hen cqh ayg tcv thc srd rer qsl hek<br />
gcy nhk rlf kkp lll cic yif gmr lil gwp
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
15. tqd prc qle gsq ret nrn qlt lhg ssk fsr dhc pph ycc iid rmk gaf yyq iga mlw vqt cvp<br />
nmi fmv gwv cvv fli pek nae thd vsv hrk pnk qhl mil kgi kkt fgy cgn nvy khr mfv sgk skp<br />
feg lik mvm iwi grh spf rpk kyn nes van qnh lrm vhq wai lwn ehf npw wvq qnh hcc lwk<br />
ymq fdw lfa yek gcn fkm nkg yvw iel rsy mlr nfk dhl smh yrq wfs fpd wak wkv qrp nhh<br />
hrf tdy tds ylw fmt wkp rfe fsn dmn lfd tat qhg tkm cls yeg avw len qef cda pkm aqi qcq<br />
aff kav did aih kyr aem fsk ctn vvs lig hld tvt igh iyn egs yev cgm wkw yfa nnw akl pkn<br />
sae stv nwe laq ftm ndv qli slg igg shp rsa sts wed crg pvn fts lkd kcq pii sll eds rng fep<br />
grk kyq yls avt qpa vva tep wka yhl pds tfn sqq evi fhm lfg idi hcv kmy lyi igs vwn mnr<br />
dkh wrm ggm fmq ewp ysw kwk rdi ysd iwk lfs cge fse pwl iyp qac whm vpn wnk aim<br />
add ipn qti gkl net lgr nct dwk kmd rdg pmc pfe pgw ida fyc egi fgd nkm vkm ynv gks<br />
awt wyn hvi ket tvf ytn eci qdp tnt kyt dcv qqa ssp rer imf dac hcl dqy kgy yky eac rnm<br />
dlq ktt itw wrk spn nee plr nhr nrp ihq pyc rhm yhw emt wit ese rey cnr nyc khs aks dyf<br />
vnw rsr gmf ssm wnv wvr sfq crl nps mpd frq sws gch qwf iim ske fyk ywm flp qsw tqf<br />
sik ect idw evr ehs lan yfg itk ckc ene wqf vgm ega yyq kfv vhh thp ewg lpq iyq gsr cgh<br />
mkd tqm cgl ywf mvq ikl ecd dcs ppw kml stp gnq mst hkd aqc mhf rch mil cmq lmh ckd<br />
ian vhv mtv spv wpd kng yap yss rvv nre tlf lic ilw imm rwf efp gph ghw cqm myw nke<br />
myy snv ctl pca ekh cdm gst der scv yfc ish vnl tlr ssr akv ycn rcc nav pnt dye nkm gql<br />
gkc myy naw wcw vwg qth atp fvd shc vft ple dlh kce rmk ywr rse gsd aiv dqy tmt fgh<br />
aqy men fvl kiw hif ilm gfl iqk knd ltv wdt chm ggc<br />
16. syc ied wll fae vwq lns nlg yyy whr dhn nye ngh etn snp ake ewe rkw kys tvf gpr enl<br />
cas ckk dek hen nys whs mfq pal glf nlt ipi klw wty vws ylk mch ivy gsd pcd inl pgk ggt<br />
gdm ddm pes lnr nwp nrr pqs giy fvl fyv fig gsf igr eie gpm ryi mak krh eii wll vfe hnp<br />
tfg fkd ski hgt yry ikr klv pqa cnn nhp efy taa nkl leg ten iqy hqd kpe ifm lag vcs wly epa<br />
hyt gsf ntp fqc sat akf gva dyv sgc nwt wap lty wyw qna efq cts tqe mth ead wqc lpc dml<br />
pgt mtn ngm hfq key slk kfq ide hmh mqg ccn dar dte mse wgw ytk efq tel gwp gte ghg<br />
ptq kyp tad nfy len cwt hhs cdd vhl iyv gyy pgc epq iwi qlf pwq ryk dfi ikq lse qfp yem<br />
vnp cne gln qlc wdn akv ici fwa hfw dde dia nah arg iwg lin pkg lmf ldp kki ipf fdn kvy<br />
hfq qwp kpf kng cvg nat gsm ttl fny iri yrs mss mns etc adi wyl lla vyp nca apv avr fnm<br />
fic irt hpf fis kyc mdl igc cat hsh hqm gwq ifr yfm eft ldg gnn raw kyk hmr iad acn lsa<br />
lgq hfa wim tmc pgp vqa igf ggm aca tal tet mhi diy mgh lvf nmw eal fih kwm ctt qpf<br />
wsn nss ngc hhg qkn pds rll pwy eqi dfe few nir nvp hmi gkv wrw ppy ffs vkd hyt lvy<br />
pen ylm pht cmk wtv wca gie wgq qge lie cnr tcw eep qaa rkf vcv nev fis mmi mqv tsh<br />
hsa vgt frl krn gsy apl emq qhq fwt wda iyw qcf ayp mdd dss cwk iig iad ids ifh std pyt<br />
tyd hyy myp ttp pdf dnw qes ndi qwf lec qqk daw qty eln qhg yiq lpe qmd psk idt qnm<br />
the vrn qfe ygg ida nrm grn mvf dyy fgk pmi nye tvw cvr hgv stk fvm yav qsy eqq phm<br />
sah isf msh cwd nil fgw gnf spf fyi hnl qqk kpf cki hfy wvm apt dsk vdg whg ymh myv<br />
rem eql wmn lcv rni dlp wsk aay qvs vqf wth aec gcd waq qrl san cmc nne prw lna rhr rll<br />
fea wel fcp dik mwd mvm ewg dli yme gfg igv
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
17. app vas twr sma hwe hfs tqt qgf kid lyc rdr sas syh ywh ctd ahd vlr rsa qvc ced pfw<br />
npd kts ktk fhg tgs wgw nrq vpw qna nfa msv gmr mnr ckt acm wci gmt pin dpw aen vhs<br />
waa wcs yhr nce dcr hdk ifd vvn dmt mhy hre fyc vwy twl sia dtc gqi akc qek ehf fmn rli<br />
cwf lic pey tqi gpq gty cmm gnl dvh eyh ryc mcq whm khi kay cev dha afy med vsm ver<br />
wln afm ppm psq git cgh ywq vsi sla dtc aff aiq esp hlk wdm fig vha tkh sfl eek atg lmk<br />
kwv twv aqw ecv eaw dll wfi tyc pvd fsp wdw gry nya hih fre dey sdd igw rds vvf sdl<br />
ekg sfa gnq nfd ywm lsc ppf ekg mdd wag ahq pdm yln ltp dfg eyh wrt ndd gve prd hnc<br />
svp ppi tgl qln ihs kee yen hpc whw tyw gqa nrm ldt eiv ahv qrl qym yfl ycm lyk edy cda<br />
wen ray eai wrs vqn fag hsh fpp las khc ycr kyg emw mep qcl vsw aft ihd tdf irq rsi ngr<br />
mer nwl ywh iyh mhw piw yhs see wsn pyn kis eay lmk smc wna whi hgh llp vym rgp<br />
qaf yda ere win ghl pwh lad wyv ghd tac dqc mgn dta lse car cvt yft esw pmt isn rgr vgg<br />
thf nsf yee rip iiv yle ete dvm gwg tmy rar fpc drl qss wgw dga yan dht emc dwd acg kkk<br />
frf wss wln rcl ygw hdn mlg sva hhd thm wgg hak vdn lhp dvq vkc ivq aca ipd hpn awg<br />
els fak vki dei ypg ivd dgd pni hhr ekt evh hit ltk tqa plf nqf saf hcn gsy erw efv amc tcy<br />
dff lrv tqh pwm wrk wvt pnw eny qev ttd tnt ckn tce dgg rwk yyt dvk cfg dqs akq tac<br />
lww ndt tcw trp csp stq why vhm tga fkk vva rwt kmy wae kgn rtd lsy lct ciy aen ydw ila<br />
pnm rqp vde iee qhr wpp slm lwa akp srs ism fck ncl ryf ftw qpn vev iee evq ffc qpq kln<br />
cwh spa vfs rsw qli nye pnr lrl mym mnr qhq atr wkp pfh ree gnt ipv fqi cdf lqt rvs kyy<br />
vey wyc led ekd sqh slp csk srn esa ckh rmy ipr<br />
18. mdy fmc hkl mrr apr tlc mqk cwv wka nfa fkl avg wrc fii hyh hcm ntn kpv dep dmf<br />
kkm tlv qra ciy iyc cgv tlr led cpf mwm deh mtt cmy inf nlc ldm ngt tar gaf sdw cfp wwe<br />
cqe mfg eyt mqs pen vrd tpp wlf qra stp kdq yam vat qfd mce tvl dmf phd fyv yhr pap<br />
vnv dsa pwc pes ndg caq ana lgh psd pfa qtr dts sdi efw qrt klf tth ekt kpw lsw qvr gqg<br />
hrn qgh qtl nfs qcw gld rkq ykc hme eiw nfq eqq dkw tqp fyw pdh esi tds tvg vvq wrv<br />
mqv fhl qdw avn nvr hme tdy fcp mwk ekl hcd adq rrp ykv hgc qwd fss ivn nfh lke fhp<br />
tef ndw qfp ngt ntw ewv klf lvl ael myh han epf gmp ihq tyg yet qam cav vvq ssh kdl gvg<br />
mny sel ais vrc gnk dpr tan cfr fde hhp tma pqs pvp pmq sqf idc qqk sem ynt ypp kce ldm<br />
kwl cee nph ddg tqa asn vld yek het qhf lkp niv wmf inp dhy vpa atn ayn gdq akt cig kim<br />
geg win ykd nkc isl hww tdi ldg kgr htg hfa fve qhc vwg gpp qip vis gdi cmm lrf her mas<br />
dse veh nle syv ltg pii imq arf frl emn ecp vvc vcl ecw eii smf yac cff wed cvi nfl dwh ill<br />
pad ena rnp yvf hny rif lmi vnc lsa hfd vvc agp akn dwi lkp akc scy cin tic den fkf hlq lai<br />
qfn sci qsa avt rtl leh sdi srq cen fne pfa lre vrn cfr vyq ahy prh eay mat vdt dtw pnc vcs<br />
caf hgd ssa hfi hhi rti mht iwa ysw vpv ssa vsa tra dsc qle gtd rlr aty nqg hhm tpq pdp fwc<br />
yws lyp kyy mgh ylk nld mag dhl snt kcq lrr gwd trf mqy vtl cev hev efy eti sdt cqd tkk<br />
gwp vyg gam ncg vty swd ale gqp src wcn rkt ifv vqf nhh hdf sie frd fae rqg cqn hrw rvk<br />
yha ggh ywf dyc hqs kga qev ven gwe wdd lym csl gvw eww vqs iqd avs nrn rlm cnw nra<br />
qla ldc hhv htv nwv awd vfs fdq qtg kyf wim dpv tps avk vni ssk kvf wdd iwe inp asa spd<br />
iqy ekg caa dyh iki sch
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
19. mdy fmc hkl mrr apr tlc mqk cwv wka nfa fkl avg wrc fii hyh hcm ntn kpv dep dmf<br />
kkm tlv qra ciy iyc cgv tlr led cpf mwm deh mtt cmy inf nlc ldm ngt tar gaf sdw cfp wwe<br />
cqe mfg eyt mqs pen vrd tpp wlf qra stp kdq yam vat qfd mce tvl dmf phd fyv yhr pap<br />
vnv dsa pwc pes ndg caq ana lgh psd pfa qtr dts sdi efw qrt klf tth ekt kpw lsw qvr gqg<br />
hrn qgh qtl nfs qcw gld rkq ykc hme eiw nfq eqq dkw tqp fyw pdh esi tds tvg vvq wrv<br />
mqv fhl qdw avn nvr hme tdy fcp mwk ekl hcd adq rrp ykv hgc qwd fss ivn nfh lke fhp<br />
tef ndw qfp ngt ntw ewv klf lvl ael myh han epf gmp ihq tyg yet qam cav vvq ssh kdl gvg<br />
mny sel ais vrc gnk dpr tan cfr fde hhp tma pqs pvp pmq sqf idc qqk sem ynt ypp kce ldm<br />
kwl cee nph ddg tqa asn vld yek het qhf lkp niv wmf inp dhy vpa atn ayn gdq akt cig kim<br />
geg win ykd nkc isl hww tdi ldg kgr htg hfa fve qhc vwg gpp qip vis gdi cmm lrf her mas<br />
dse veh nle syv ltg pii imq arf frl emn ecp vvc vcl ecw eii smf yac cff wed cvi nfl dwh ill<br />
pad ena rnp yvf hny rif lmi vnc lsa hfd vvc agp akn dwi lkp akc scy cin tic den fkf hlq lai<br />
qfn sci qsa avt rtl leh sdi srq cen fne pfa lre vrn cfr vyq ahy prh eay mat vdt dtw pnc vcs<br />
caf hgd ssa hfi hhi rti mht iwa ysw vpv ssa vsa tra dsc qle gtd rlr aty nqg hhm tpq pdp fwc<br />
yws lyp kyy mgh ylk nld mag dhl snt kcq lrr gwd trf mqy vtl cev hev efy eti sdt cqd tkk<br />
gwp vyg gam ncg vty swd ale gqp src wcn rkt ifv vqf nhh hdf sie frd fae rqg cqn hrw rvk<br />
yha ggh ywf dyc hqs kga qev ven gwe wdd lym csl gvw eww vqs iqd avs nrn rlm cnw nra<br />
qla ldc hhv htv nwv awd vfs fdq qtg kyf wim dpv tps avk vni ssk kvf wdd iwe inp asa spd<br />
iqy ekg caa dyh iki sch<br />
20. rvw mmk aef wcr tpk rvd dkr qev kti wqi alp ikr yap grc fnn hfh csy ned ccr ddh eht<br />
ipm crc slh pqh mdl wcq hyq fmv amr gqq lqa nkt dwt gqh nnd cwl igh dge vlk ank mcc<br />
gvy rwq hne fsv stf lwd kld fgg qgl ssd eyd eit qan dlp rsi vec qlk gfl glw nay mlg ynv ssl<br />
ise spn mkw nkq gwr sll swc kgc pqc ryt qtf vsl laq irl skq vss sdn tlf hgy yty ivf yes eps<br />
yim vyd qiq fwv mcw ach ach myr mts ini gee dtl fsn pqm ymp qpt dig fep qkf tgs fqv<br />
ccv lll vtq gwy wdy vcr cyf ree hhp vdv ydr wql qar fvt ecr ngv dcp dis pqn kii efc fsd<br />
sps maf sci pwp igv van mlh vth msh rnt cre dpp wer dka crs mve dcy ynr ima ich ena<br />
has vtw gkv acp ste naw smm hve qkr vfw pwk tvy cwn yyq rhe chc hhy nyl ncv shc cck<br />
ppt ers swg nfy ray iks git eew ltr wym kvs lnr clf hma saa ecl khs crs csh irn irw mad<br />
hpm yyp pfw dvc mgq kts yyd lsy nek kpw ynn kcw nmv ynq nnl qcd rah kyc vvl qmc<br />
aip irv pkq vtg spy avi fst pgc lyc rvi gsy sdy rgf pky fsw tlg ald tln lyn hyh hrr dev het<br />
ltn myl iic rvp wks nrg tqn iqn tng wsc fev lvs skc pgm raa gwa nps sfh qap mla gqa dem<br />
mck tfl vhh tnw nnn knw esc kys qcn vtd nfn gif qeq ghh llg wii qqr edq idc ngd wsl evf<br />
tsi nny ehv ylk lhr qly plv nwl adh qle lcr isk wpw ada fkf mkr tka tyh qwa lfa lrd gks yst<br />
scy vaf fhq wlq wdr ens gqs qfa pta dwt keq gsa rwt esc vna ang hqr alq qap gcn dtk hng<br />
fph hpw esa krs vde vgt psy vsm gpd ftr wik nhr fds wdr fms dla hac mym tgm alq dtm<br />
tyc dkt dcs lwi mvf ipy ggp ppw tan lwn mks kkw qtt yed yss dqy yam mwk yqr yaf icg<br />
nre tgk wnh lwi shi dre qai dcc gem ech mki qle rrt tgg hqq faa wfv rvn cps vmm hhf hch<br />
cvn ppc mmg twq fem dke sdq dtm cmh
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
21. mlp ksv qki its dek vmq tfs fhw pyf dgm kgc cch eat wvw qde nkc mck pwn gqk phi<br />
llv vge whq cms rml kyq wqh dhd yyg ftm hdg pnq lpa wiq yqd vyp wcm hdy aiw mik<br />
fmh tgd hhv vwy mck lcd wpy qcm ddt trh tfc hdq kqi yhp etf die akg ref rem wpy naf<br />
srg gas vdh ifa aqp khr edq vga mqf pkc idi gtd fnl ads ghr ith iwe hvk smn ddm llc qwt<br />
vpw qnc lfm iqc cpm dfn kih cil err lpw kmk lma vca tft mkc yck rig ili wps rqy wtg vti<br />
hye spw kny hvd rpn gdp gni mmd fdk gdi iil cch vyc gcl eki vwt vtr wiv glm tev rvc crg<br />
vky snp lrw vah yta cva wns ekn mdd cki cke ndl kfv vgm qgq hvm fmd gww ccm rcq<br />
vvg nce fek iys mst fpl qvl lph ics agg ygv aec vrc ery kvc wti mql kqm fqe tgk inm lvl<br />
lts dnq mvn yia vql irs hef nyy eid fwr hhf ren mkm eqv fhs fnw tat rnf wwl vtp yvh dwt<br />
qev erm dnw rmr lrd rfn wmq qpm edg thy efs yrn nfh att vln rvp qqq lte fke daw tgh ete<br />
cfv qhp wcy dqt ahn deh lgy ysq yqi dpw ecd vyq rny rqy hsg tly mym cyd apr hvl ava<br />
dyp siw eaw kqc wnm qsy nsf ffy ihg cet pws rhc pds lin sgn rct ptc cde pkw rrf pik pge<br />
eqg vak qdr dtw ada cln hts msp mkt qsw lca cgr dta vam fti pam cqq lwi iei wgc enr<br />
vww nma fcn agl kan kny nmw sgd rhq lkh rsp gcc wnn vpy saa glh rfa evq ehc ssg rpt<br />
ign ndi rvn fyw ada mqd iiq hei hit dpm lck nes khg pye yea npp csl yck lwg ywy dcq<br />
daq kpy iwt agh rmq hyt ihg rha gqk nqv efw lls ndi tmq mfy rga lks pce gyw pwi ryl tni<br />
ehl nrq rrq fda wkm cev vvm lvt acd qlk lll erw ens ygh arn dgi iya lic kff nyy atv inw<br />
kwk kmf ykw apy sta sdi nsa wke ykc tke pmn qne ywm pge fvd ldk vya ydq hef lhe gis<br />
wqn hnq kwg ghm wft gik ewp egk hkv hcp gcq emd kgf cgq chg ciq<br />
22. gia rcq can fhr ipa mcs lea lcg ehi tkg ysr rri qdd qyt imm teq elh vde ahy ilf wpk kew<br />
gvq vpk pcf hqg pkv rsn idl riy rls wms cga mwd rqv seg grm svh npd lnl vmk hvd wsc<br />
ild nfm qcw gpl mft mqn gsv pwn irr fwv npv tai viv cyv ayw drc gpq ent syt sta eca ife<br />
qip qpk eta eta wme cqt aws gkf idv awt hni aqf nre ygh msk sna rgg vtd dsh amh enk<br />
qap vsh sst wdp tpn tsf rcf qhe drf amq rrr lfg kkp llq rry rgs fpk epi dav nyd kgv dkt icq<br />
psd lpg vpg hhv efa iic dhs evn yrv kri dgi gmd wcf dqy ldc qll ecc flf rfa fyg mwa wrh<br />
ccf wsy der ihn hgq tng ipp any gga tfk hth mye peh gwr wkm wff pqv ngd mrg qsn yac<br />
ged niq wdv ayq vly est vgn atp dew ftc vhp frf pgy vhy mnh ilc hsk wwq gqc kne fdn<br />
ygp hcv hry frg gsf kdl fhw qdd tyy smc ewl kpg dgp cay nyp pik pwr mli gal csr dnl nch<br />
qnn nti gch rqe kts nvl crm mrw rrc vhg yfr qag ltn rlt nms tgr fpv peq iae ptl fyk tlc rrd<br />
dmy nng vhg nfh wtf fla iqd wrt ptf dts hkf qdl wfa nnm ard adn qis rvg ith div cke ngt<br />
lsq san yki wel dds wqn dci pfa qvc qwh ggq cwy yir wfy seh rfv pmy qan dfc vdg mmk<br />
dqa sdr vhw lnm hrq aig ify idy yef acs mpl yei vqc ctk kiv hld rea wqf ens nel ktw pcn<br />
eai mgf mqd cgi imd yik yfr skf aic nln vhl lgm pea yqg eak kva cwt heq fwr hvy wmc<br />
fml skd gle srq tkl esg tdt twh qat ghr hwr wir pvf hvg wny vrl qyl eld nrv inf cfv ndq cqs<br />
nqy ify vma mye qee kks twc htl nhm thy dgw awp iid dey pfs ges kss lln hgp ngm mys<br />
fhl tng lkm ttk lmd pcc mkf fyg fhm wea fen vew ipf gid hkt ilp dpd eey lgt lrd hil lpp lqh<br />
lqr fis cnd iiv ldf clg tle tsd dvy nmc yty gky sir sya wit mak qpv spk dvw tak vmm peh<br />
mep ycf spw qrk myy myq kng
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
23. med tmc rmv sra smm lpq sdm pcf rqe evi dpm fff eiq amh hwe ntm cer stp gwm wih<br />
dvn ikw nrg ktk rql cql qcl cwh hqv pmr sve rnq avp lpv sey tsp sqe eva vsg pqy cat ims<br />
aep psw ydf ywe fnt qkq vst lsp fle mcv edn hev lac efp slw yse wvf nha fnh vap whf drh<br />
wvl mvk efs fdm dgi mym sdd tfr cqh dek atm rtm hca kyt mhn sae ivp shq yws lph itc<br />
vqd rdv akk map mmc ggi ays pel lsp cth adt tmk wmy mvs whp iqd ceq npm amk plh<br />
hdt dtv tan avn aeq vcg dcm lkp qyh vel ccd qkf hhh nic inf pfy nwn nnt afd svy fse cma<br />
ire qiv hkf edd lvg gkt cmn ydn lfg tmy lam tdn tvq ifm trn ddm dnv prc lqi kgc sth cww<br />
qls yae hwa rwa hef fpa tef hka sis rkf sfv slf tra yrc qtn ddd aym cwe esq yas qtr ntg kie<br />
vvk krn ssn eil nhp gek rfw hrn icv pgh kyl lap fps lmh rie hpf fds cir faq lfr stq pyn yhn<br />
pry mlv cgy ire hnm pge rvy flr pqk mle kfc agk aci awf pmr aly dkd khg ypv mva vfa<br />
wid pii nla ltg kiw wck vis fsg rtg myp hrd mlm all mmi cmq ivp ati whg rya qfp ncc lsy<br />
cgg plw chq gik hlq nna lwr pet tay vdy ffm nsy isg rar ges hsw qyr eaq icd fcl gyq pwy<br />
ldk nqs vdp qsi csh spq cck ylk iqp mcd vnv wsg pmv hme afs fyi ysl eii ygt ker kel hiq<br />
dqw ish tll pdk mel ctt wka dvn hci ret kye eai vyy nyp kqa pal pdp rpv mef wsn ctg mim<br />
wcg vyq pqw nni qsh sln mya ehf rhg epc ekf hlm crk ewm knn htv nqi apy tge vyp ctk<br />
gmn tac fei ehg eeg qld hkw pgv whk pel vyk qqw hsf vdk rrm gcv sdl qpw nke mmv qnn<br />
gne sne vfg frq rqg rtr rih eme vvn vti fid qtk cqm rgs grq aev wai eyd ymp sll dvh lvr<br />
ayg hpf yph tnh hce fpl wcv ily kcn mpk tvw hep ilf egr qlf hpv ryy hfi yrs kwd mda mvi<br />
ini nft ycy lhw vge fpm ckw hac qcn asa<br />
24. knv ihd qvq epf elm ifm qmw epr qry lec dke png gfe ieh miw qnv qmn kch hlv gst<br />
qql gmy pgl ryf kmc nsc rlt rdy fhf efk tcs las wyy rkf lmm fvl pes cng tfn mvh hsw gpa<br />
khl aic mig pdn wwm pic tgv mpr lhv ece wdy vid snl dcw igg irl lkv gti cmp gql ffa qhd<br />
qfn flm ric nna pmv hgg wgc dgn lrv nvs kqc ysv act sey fqt dpi ntc iiw fcg val ils vmq<br />
kmy lpt itr hpw aal ykh lme pty cit ypw mwg cag hsi egg yas fym ril gfc kme wmk irp lrd<br />
wrf cer kak pmk val ige qtt mmq ivs gyc epc cqk rda acc alm dqe iyg fmi wsr grc dce qvy<br />
knt kvn wnh gnp qlc ell wmc eep rnl wnv mie mvq dew vcr yyl mwl lfr qka int qvr wsf<br />
gfk vnt sek clp cst crd mfw rtn ern kdk fka gwt paa kkr wsr elc ged gcp wdq stm wcw dec<br />
pgm gni mdd cdv lpy wei svk fpi hlq fed hdt mpn qvi icl sfl rmn whl cmg scq kfy rkd cyi<br />
ltk npk rci irp ddl nil rpn ptr ieg dpf lcl pwc psn sll svl ypc llv iay fci ndm mwq frt crq<br />
wlr phe qdf nap nvp ilg hrq mah vrm cqf khk dkk des gpk irv nyn nal ggp fdt idi slw wly<br />
wqc aek dsg kvq svn kdp fta ymw qli ama isa pdn his wmm rhv gsn wnd kev dgh fvs rfp<br />
fdm mfv hvr cvv dkp ygf aew vts tys rvc msl scm rha aah tli lrq ysr qpk laf pms awa wfy<br />
pnc ctw cth vvd tvf kht lqh vpf qqm cty hsy wwn ecg eac rmh qql rgy dds wvc yac pfi<br />
nvc kfe ffy tmw nln msn psp gqv chy qty sct mqs his cek chs dch tit ant yqe avf ahh gfs<br />
mvk sqh ikl ali wtq lri kaw tvq kqv qtv teq wrt glw fcl rrc vsn asd kll int lfe vrp lwf she<br />
smp vpm qea tcr ppm acl ppp ywk fpt ttd cll ldv ric nsl whq sgc sff imi wgt qwm tnf kld<br />
fyd fgw mwc pin fwg ysh qky lyh hqs hnw tcl mgh sck sdk cmq vph qgf qkv hyg iep vdl<br />
gnq ven gas hpy kns dea lgn kfp
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
25. wks tvd mrn nwg nin cyn fgv qtg eff kvh qna fkv ktn neg eqc ehm pif iwc sng mwi<br />
emp nen yie rwe yqk imh tvn vkl efw iev yvr mtw ale qqr tlf lhd esp qrp hhp tfe sai gmd<br />
smq mkr ksm dth kem wqw kgi ywl gdq sqf mry tqt qtp pet tgc eyv ysv csd tvy wme pla<br />
ygf tgq kcc tpd rtp mte qyi hde hwh dda ifp aev hql mvv nts eyn nwr heh tsw epg env iwk<br />
raf lni pgk npm yms hkw hmm ggd wmr vkf pap tpe gwq fty esp phv tcc ikk qky iwg pyh<br />
qpi kar kvv hgg yle sem wrt wtv wsf vam nrq iwn pgs hpd mfl krl rii nqv kav gpd epc<br />
mmc qym eed vnm pqw qsg igp ffa ghq cts wnt nwc thh qdy ndr rmh ehg kqd yny reh gtl<br />
ktq sys ilq itr ahc itk lie ktq raa gfq amm cnp lms pyk set mfg dvp edw mpc mkc kte qek<br />
wgq yhg kiv the ywp wcq rlc wqy saf hpl rhs lqh hqd sim qge qgp wal iif myt vyp yhm<br />
rre hca ivk gcd apm dye cwr ivm qnd mdp pyh whn qhm knk qhs icy lel dis gvv iyq haa<br />
ykm dle fhg eci mme gwp lma nnl nmw nrv rqt pmr eav hek net scc whv lvs wht epi ani<br />
may ecy yaq gaw gdf skr fvy raw nnq hlw nqd qtt hqs ihp pik ysp swf mka qfc ecy dlm<br />
lnp wdq yvf frs lcy yvl vkp kep plv vat mpc qwm ncr yae rdd hmg wht lmk fyc sya kak<br />
afv mqk smt gfs eyl cgm wtm tsg mfr iac kdy rwr yfs wct nak rde yna imc swl nfw cin rlp<br />
qqq mkh gtq nmd dcp mwp flh gcc fta ktk tdm qpg twg mhk lfs scv gvw ief dhf srv tik<br />
fdi shf qma lle fvw ipm rct cvc fmm clk gap syr khw sgg wpa elq lrd vmh rap mgr mcv<br />
egt att ied scs epd ele ggw flh eel kye nim dhp vaq icq ahm ket wqv svf iac kgv lqn pqv<br />
yss yhs mck hkl iaa sfe cwi wdp seg qat hwg isq adc hag htg fip gcm clq taf dtg pqf lrn<br />
mec pkl sdk rmd ydd elk awr anv vhk ifc ygw fnh wwa tpc qmt yas dga<br />
26. acv tya cvq nyd grk ycm rpq sta wen vlv ynd cas ksi mce ecf efe qqa rgk gvv wyh lvp<br />
ymk dhi mff ksw str iey nge arf wtk fpw wca rka qdf dga llr ril thq qdm nmp myv nlr eda<br />
cmk fns hhm yvk sqf gff wfs vdy yqw ghf mfr qqk tfp pha kev cnq spl ysh qkk hnp nht<br />
tyg myp vng chm tfc cpd sev dqd gan amf pas mva kti nlq ccm wkh pvp enp dlg wfe lat<br />
sck dst tpk pnt caw hfa fck ypd lgi app nfr pii lrv rgk wet iql tek kla mgl eev gsr mcp arp<br />
hhk aaf fch wcm nkc fnh ihy vlk fpq fhf rwa nll fkg qrc nfa fyf dgt gtp wat lvl sde eeh lhp<br />
ryp twd rcs dlv gcp ecq dqt cfi taq igq tgm qqk htk enc ssk mwt ffe nse pvq pwc kih sfr<br />
tae gsq gry pvw fwr sdl iip wes rdg alt stm ewy dyv hha etw fqw hyq lyl lsl ncg acr frl<br />
eag sgi isi veq gph eht mwe pqt cgd iml nli gch dwn ghd rwy ide pyd ycq gat nsi wtm<br />
hpk grq raq cnh gqd swh aaw fmt mfc fek hfw dni wim sll plh kyp sde wse slw wpi chi<br />
mga kcs dmv cee eea nsr inh eks rte eal eiq gtd fky avf mgg ima pfg gny vsd mnr vqt lqc<br />
cil shm aih ywn wqq ndm gac chs dwh nyt tym qgw dyc kld ddl dqr qnc lea wwn wrt<br />
pwn dqe rdp eys fhf kpv inc shy rdt wsn ega qig ydv nei ntc gkh aqv iql yde php vkr dem<br />
qsl mil crm fdq wsr qhq tyh sar dfw eit pcy qdh kyr fpg rdi kfg plh qky fqc gdn tmh gmk<br />
igd mci hlt vgh qyc dpq icq ddn gng wmd qrl hkc etn mmm fdq chv wnl scf fmm fvf lyg<br />
ctw vhs kii dww sqm dsg rgc qkr qkw yhp ehw mer idw srg dvv nga qee ncs veh qmg ckd<br />
mmk cnw mdg vea crc qpq ilf lhq cwv een gya fsv cqk wqc cvd arg fpm qye ica lpa vsp<br />
kvh eih dih yty llh ivt cds npf anl ssn aql msg csr cvr kvc wpn ike mna qnm pan hnl drk<br />
ftp tyg wsy wrd vqw knf nkm tgk ema nhd gcs vmv
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
27. ycy evf dya dts lvr hnr ehy anp ygf wdv ecf cpv wfm pci nvi ltw yef hkp vvw mnc aer<br />
tsd ciw srn fya fng wth gce eki lqm rfs kws lnr wst vyw lni elr fie etk qmm kdf nkg isr die<br />
fsa qdd mkl eeg iae wwn tgy yad rvf dke fps pei yvq plf cny pca yph twt slp gpi nam gdt<br />
kkl hvn pdn rsr idf wwp cva mme swt tan tvy qcp gse aqf iak ykw vsi emy apq ldw ely<br />
mfh sen rvq agp rtn gld wgf gpl vtr cfn qch flf aki avh pld aqa vfn dmm dhn gvh pmw<br />
had mee kap twc pks ips lln hve pgh arn lmh tyw cdg adv vrp ant rev mvn swa hev sid<br />
imv ckn gmg pqf mky qqh eaa mey glf spr vft haf vvy sfr ycw qqa thm fte hmt gwq tgd<br />
pem yfg wvd kle dkk nkr sis wyv ciq vav nli cgn del mrt kwg apa knc qfr qcq nsq ncn lim<br />
mir tny eer qtv fyi mts fsk kec eqp qya mgq fgi snr pdi ght egv vef dkg kfk tcm ced dmw<br />
vsi yce lpi mgv rnn kcy tse rws isg tgv apg haw agq ihp mch lmi nyl sfp tfg piw spk grk<br />
gcw aif yav pfs alr ita niw tfa gae nvv hgh wcp qnf cda cti pmf tiq lre wwk frv kpr lhr idf<br />
rqc fnd cdg lav hwy dny dnf hlp epv erh vyw qvv gdm aww nfr iwg hvi pep rpv wqr phh<br />
arg lle yfp irh npr qgh gwr wnp pde wvy gye npr iar nrf lch rcq ylk dfw dai rkv vdm stv<br />
mva paf vyg qml lag qer knp tcl cet hct rcn dkq sql fmh yiw ghd hdp rnk nyp qhv cft sfv<br />
rkl lir dle gke yct shw qte dcm wha nmv wna iin nga mpr cfr cyg dpn gda tmq iqf htv aad<br />
vav yit nhq hnr wly mwm atv vle qae qav ihk ktr pmi fce tlq tly nnd asr ern prn iik prc<br />
kly imh ryf cyt nfq hay tlf ppp ppv ydp svk pph gwl ysf dlr nhs kkl nne rwe gsy niy mig<br />
tgl let ryi dgn lqm yre wei hid ewd ghv vnc wss nsm fyk eri mym hsq way tws rkg dky<br />
dyp qyy etn vdq mtc yqc gwg hyw rhw<br />
28. kdl vnn tpm dht ygs dgs qhf prp qgv aim agf msv qqf hpl ids lhg nhm ynq vwg sva<br />
cdp mep rmk mve dli ksm wsa rev mnt atd kvp skg pcw scm irp qgk gka ldd hrn trs efp<br />
hhc nty prw ptr ymv wwm rph wvd lfm nsi idf edh fhs nqi dpl dqf lrt mge lyp fck icm<br />
qhh dtt hkd vgg fhq kcp mmy dfv ckl dfe tqy rem lnt cpc spp gpt dkp pkt svr phr ifv ymq<br />
lti ekq pmf hiv gqy hyr phw kkk dpw dtf wym inl fri sls aky cyw yap gmw tey kfe pts lqr<br />
erp fwm mkq fti csv iqi kyw etl did gif wkp lrr egd shl tta csg alp pgy dgy nrr tec rir ftc<br />
vgp ggi vtt rqe prh iks vqe caf mni qnr ark ife scr hdw wvr hyw rvk kgy rav aty sqg ave<br />
tdv qyh ila wlt ker nns cim avn vas pff mly tha wrl fmk lqf fpf fdd lma ghs yfd vrg qta krl<br />
rpt fni ekp lph ihp yfg caa ndk lvw lim hpp yip gpc vyd pyc tlw cdl lse cdg iys wew grl<br />
tac ngq vgf dmm sce lgs ngf ktq piv fpf vhl ihg fgl weq piq hka dwp aek ffw rqk nvt lwk<br />
ayn tty htl atm ekl rdc fkf ind mef glc rgi dyq wmc smm edy swk glw kkn ckg gyh vgy<br />
ygv nps kpm qnh kah vrt pag vpq tmc mik dyv keh vki vfh etv rtr cwf pga nqe lkv iei nyl<br />
ykm dhl qqq pkv nni ygm yas ngg csc flw nln ift sht vep mal hyf qid dnq gfy cdf pfy hcy<br />
rfg mpp rrw lrh yeq wfd cnr mpy cmt adc qyd ykt dpw til mey kta ypr apl knm twp tys<br />
dyc ceq wen hvp mpd ikv wfp nhr kci hwa gwr hss twl gtt rfa thd cmg rlq lpe dqk irk vqe<br />
iwl iqm fnl rwd yne iww ckk rah kmc ssr mky qpw hlt alf drd was svp ykf gdy wqw anl<br />
cny fay hfg dvk rnm ntw lce hwy ndt rwh rln ips ett lec wcv fmn qcw kpa gyi lrr qmi ais<br />
pff cii riy fae syn ewf kiy qnm mgm lqw grq tie vff ldq qal mrt eyq vks ihe lkt mms kqh<br />
ilv ctd tyq tdl grc flg ayw iww dyk
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
29. wki cwt pnk hnd kak rii lpe iir aat pih siq mat adk qpr wef apy end sqv qdv iic ahc<br />
nyq tqg esm vmk ycm nwi tgd ews etk cvf ksv veh hga lap lld nte vqk lag sit plp yfv ncg<br />
mqs vpn ehy lwd kma rey wlq gfm phh ske lrd qmq nki qie mhm nhq nkv pvr hwc dfg lef<br />
hka asg hkh qte rit cls yql nsr ltt mrt vrs isw yqe tii wnd gkg hhr cpv liw qai isi epi die ait<br />
che frd rsq tck wql giw apm ngg qmr das kay dhv wgl gfm sty nrh wdg kik ckl qme nqn<br />
sst wdi nqs gyr pmr hlh swn dqk rcs emd nlc dkm epm crd rky yaq kcn ngw kks qna skh<br />
lef whs wia tlv phw yny mai hye rnv was kns dhg wim tii mem mst chi dti gac qpv ypd<br />
prl nvk kgs lfq drd dls ins whk gir ggt rdm ngp sgl ggr pgh lkt pim tdh her pph shs scd<br />
mld ikh sad wfl ynn vwm gtp iyp ngg hhh pqv gfp gnt hyk rcm css qsw yhk ktf etd nat<br />
ksy vrn qfy swt eeg qyq wdc mvt tms hls nty dyq gqw vaw dah scm wkh kfk kgw dgg rtd<br />
avl wag gct lsn fch dya gsm kic qif wcm dwa vhe fsm ngq tiy wep lqi hec yim wfk gne<br />
pfn fyn pgy dtf hvc iws nae awq iqc wpg kfg iff qgm vck tvm yfs pcc lvt fai gch sqr cvp<br />
nti mrk mhp atv asp ifl kiw pfa wwt kel kfd nms vcm yie knf hnq myl shm imp pvi fwm<br />
iqm cve gkk mef rgp shi hyk kph yce enc mik waf svv hhq ifh tgy nas ynh cek yyv lkm<br />
vvi fdi sna mlw klp ypm tvs kfl qtr yvn lnf syc sdv lmw ifc kps hdy tcr hep rsh pfa kmg<br />
chc wgr qdt ppq rrd apt cmn nin qrl pih vhq fyd wha kvr van qvw gdk yrp pyy wnt dwn<br />
cwd qcv aiq rkm vgg eat eig eta fhd hgm lpf lsp pyr vri crt nea rlm reh vcf ahh pvh igq<br />
nrl gwp ypy ppn esa efg afg ccq gve eyd wsh fkm hqh mle lnc akd afl hrh dls lgf pes<br />
mhw ivw gdr hny ksl ivr avg adc arr ekn sid drk ies iya<br />
30. mvn eiy crs mfl dlt csc gqy ssr ghg yhp ccr esr riy lte aak gph wes gta gqm vga fvm<br />
pwg vqh evn yfh tln rqw ytn sts iws pdk ypa rtm tvh pse vgy tnv ynl qpk kyc khv qky<br />
msd hip glv lct ymh qnd syn hyy mng npa iir mcm frp atq tre ewy cwp kgi egn shr qnw<br />
tad ead mta ftk msy sda ryn ycl skc tgn ric ftc ais lam snc gmw swy rlf pap vyf ipp aih<br />
dkm erw idd qsd iyp rpn lfy qyh mfd ach fli rka lmw rer yvm ham wvc nil lge awd fwg<br />
tvr riy vwe fat tyt lec wnw vvv aep ali lsk yaw svr dyi kqw def isp ghv hhn ism wrf pcl<br />
gpm tiy gmp kcy mln swl anf ehm dpc kgd ehk few lmh dmf kqy yer lvp pfm yhl evr haa<br />
tlg yks nly hdk ayy dkv ysp wmw neh ivf qtc mqa wma rmw nng yqp vna yif gvl pcf ase<br />
wri fyq nks isk dfe tdq qkv eca pdq wim yqe eky pai shp dvs tke sew iyh cmc wwq cnw<br />
fsq rss ynh ynk lgg tsc mfq thd vfe gng gtd vhm dwm tmk hsq sqd lym ckv rhr iqt fnl akg<br />
eaq iqc mgr hmc glm van gnh klm egr vhs mrd crm ylr tfh iil alt yyh tcq elw nss aii pwr<br />
dga akd inr edl ihd kne qva dle isk ied tmg lqp sir vwc qpd crk ssm ecp tfq eny cip tyt rks<br />
qyi mlr hgi ttt igr lcc fhr snp taa csa hat tga cwn pdk msd yin mml crw gid inr mta lqa lvr<br />
ynr lyc qtg lkr pdy krt dnq emi rkd vke gwe dka mlc lyq nvw vih der tlc tsl yhi kgf dcs<br />
gqr ahh fhg gdn akd rvc dhf ccp rtr ylk awa cms vqm afc cgp gkt gwh kgy ldk pme scr<br />
wph ipg dde wrf dcm pdw teh mht cnk qvm kfd ddf gli rhn hrp dhi fpd yih qhs dge cmf<br />
vwy kpp hrn vdt fqp msk wec fay dtg inc hsk qlr wge khh fpk adn cds mem nte hfw ghd<br />
tip hky cwc qpp sld sgm gpt rwe irm htt rhr ecr sdp epe ifg nwd pes rcr qgn pad rfs pww<br />
esi fmw gqi ham eec gqi nrh crf mqc krs pas vhq
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
31. wcm vfy vgy ivk mca qiw hse tpm kwm gni amd kcf wmm kct irp ypy dmt amp lgw<br />
lch mqs ddi pqf kwi rvd dll hdt kda aet lsd ryr mfv ngr vhr wlh hhg iyi pna qsv yqt kgf<br />
vvv hrk qsi ctv ped imc scc dgh hnf grt phv hai prw pfc tkh fcs dik wif lkt lde nlh tkc man<br />
cvi tfy htk khh pmp yeh man gat hsc hnh ltn mmg afa ygm hsi hrc vhn rcf wcd avp aet vrt<br />
rhl lys psm kme rqd mcm cre avr mml pgr qip ecv adg wrv ivm frv idt sqp glh qlm wyk<br />
kfs lmh gkp rvp vfw has gfl phh ypf gen vnq cft qdn mgi pqe wgv kpl ply amy inc ewk<br />
pdn sqg vhd cgk feh klt hsc kwe aad kcn cyd ylf kat qia ggi cpy rpd nkn yih dvi tis kyr<br />
ypq rfa dfi lpy mpk vdv qph cvr ypy ppr dfh lhm fgg hpt ylm meq rny hme wyn ydk pdm<br />
tsp maq kqi kfh hqs lac sas hqh ygk tee mgv pwt fws iet ita kts pck lyi aik dvf idq kdq<br />
amq hva hvq pkl kwd itl gte qie tac pim wtk nmv vap ddg rra dfp lsi gdc rwf ctc hlf phc<br />
irr mve ltq fha sli laq glv cvm snm qft vkf tnc aeg req emv siv agv yhg iis scq ekr lyc rhh<br />
htf iaa wtp dig svr hcm lsg ykv akr lvt rpw rfm lwn lna gty ynt ewt dap anv hac diw dcy<br />
npl idw els vgy myn nrt iwt msl fvf cqy kts wrw cgn wlp yrc qsq ggs qmp sgn tre nay vtw<br />
dma lfk lqa veq qfr eiw rtd ivl mlw mwk wtn hnw reg tec emc rew gfh yen scd fvc lkw<br />
yhv hdq weh vvt npe ger did srk yms frp wrf tiy div ppv mip hfe dha hse dfl nac idn sff<br />
qef mwr tmy tha qvp psd qft tcw nnq ycp yaf ped pmg prn sdf icq dvv rcg ncl all wnn<br />
vhg ery ews wfn htk lsv all naq wse nny pdr ccd lcq vhy lpv mrt yar alf dgg vwh rqt rke<br />
sql iaw ycp krv vdm mff pmr eqv kyf myg egi vak kye cns sdi hgs vsi cqh eir rae cil ign<br />
lyt tmk qiv amt yer fhn yke hki knm fef<br />
32. acq wfs cnw aqf drw evs gkt wvc whl yry gyq vsi epk evp kai syy klk mqr tyi vmc rif<br />
ykm sma wrr sfe snk yah isg hgh tdl iwf qgl hye ewh ffq qrk vga wnw ncw wee dlt yfc<br />
rqk kec eca rsp svk lln ykm iye kig rlg end fie hna dwg hvd gpr tre gww ckd tki nsw tce<br />
gsh wgl tam dmi pkp pvm wqs vad mqr yrl vaq flc ksi pkr pka pph gmi vlp nlf ces evt<br />
avd cil fne clr ifv wmc kgn tgv wdc qai ffs dqy fts ilq eey ihh pww ivm ikv svp wvw hlg<br />
slp tqg taq ckg ytl lhs dnq kfq rtf shl vds wvt qkf pwi fwd svs dvq nmm cnk myh nga fmn<br />
pnv dnt mee iwd kyi wvp syk adv svl ikk dkp gdy qhn nkr vki dev pei diq ymm cek whn<br />
hsm hvw lms tkn gnp dkl ksh riw wpe fmk vdi lcq qhk slp icr vys ptl qym pmw hvl fvm<br />
wvd lel pma pqa lnc rgy mvv hir gel akp tft ena ywi qye nmp ssr lpy wmt hmg lnh wlg<br />
mvg kae flh dgv nws hmk qqg ptw ped lma ycw rnn qqw tea vks ers pli qps any qcq iyd<br />
gci hsf iye wtw kvd ken vsi fiw phh gpv cwf swv smp dev elv yvq dic ymd iwp qmr hfp<br />
far clr fwe slc lil mkv fsp lfp ckm app npt dks tqh ymg ihs rsr krq rkp edk nma lel ihq esi<br />
eie nlr cwg neh srw psk npe qsm yda alf gsp hry iik hnt ehy iwt mtp lmq efs pdw kme vfh<br />
mqi mrk ddf ihw dmw hkk ihk chn fvt kvn enh set qvg wmc ifr naa rst mhp ceg hkq pvr<br />
qtl yre yrc ler rik fkp ams vgc hyt edn rfc daw iqr cfs vnk qiq peh nra swc mdr ats cpd<br />
pda nvg qcw kvh dyr lpk kwm ywk lks aew wem glp pcg nfk dfw lwd fle knd liy ffv aed<br />
pek cat gil kdi qnn rry nqp vts qtl err psw ksw akn fgc whi wnn shk rfw hyw yqc vki qqh<br />
trn dla nwi rrw cna hwy tef vec lrk hpg gma lnv snc kmi vdc tgf nmw ynr lvy ggc tda iyf<br />
nmy thf dha hkn gtq efa swr hww egs vpg ndd lqc ciw
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
33. gee nta mly rnv pte frd cga kar wfe hvq eqi ild ntn ynd ykd ngl lyd ehp dqp tfl ifa<br />
wkd wkd vce cig dsl hlt wqf qwg vlm pts lyp ktq ryy vgm mdk nvk rvr trr avm lcr lqq<br />
ewv vmd lyf khm vkl tif yep paa srh kqq ftr tcc spf fci ywi gqg ssk gea eyf tdi pet eyg fdf<br />
pqs qsq pcn fhq dsm nnh rde lvt nrh dmh nmk gii kli gci gqq mrr wlw hlm qkp yeq hmm<br />
tag pmw gyf tql tae rrk nsy qgs eal cew srk anm cmi fip qrm gti qha dms fcc erg cll mke<br />
gtq nqh cym ava iln rqm ady eip pdn yit ygg ktv fsq lgq dfd mae nkc qit dya cls wgi slr<br />
qqs aff nqp iff qer eaq dwl pwa nrl ckm sck ylh krf eiw ygc dme mdt ikh rnv stq iwp iml<br />
kfc klg dft mqv frg icl fsl agq key dsw epc hgm ttr htp aae scm wff cqr lgr iff klv yka mas<br />
nth fmk kyy vvh dyp lwq tmn ewt eah dcm anv mqr qae qhc dwf ine aqs rcn wwk mtw<br />
prm ley ngm qqc mpq lnn kem rac mha fdi nnp wsm lqq kll rmg pgr mwf kns wqt mfd<br />
vgq awg vgy mdk rkd sck hgs hhc nlf dyv lit eec dli vkk qhc tvw wse nat mvg vni tmw<br />
knr vhe rrv crv ice kcq ntv spv vld iiq dcd lrf iyp qwi vsk cll llr whd dcy kfy ted ehn knk<br />
iip kdq yqk tts ial ppp sii ihq dgq vhd paw imh ggt dpa lie sqa sng khm rtf lic cfn tkt gei<br />
wni lpw kck nrv ddq tnq yaw eym grn ttq rph mqh vkw gyd kty hmm twq fwn dfv eet ppt<br />
qiv qda qpl nai viq ncr gke cvy naq lnv kqf lgw fyl dyv fas cyp ndd tmq mmd wqg iit fdr<br />
pft ade isr qni ege fqk vnh kqt stg gem cys dek sfk awd gls gfg ifw spn iwe dsq ard vqh<br />
ifh aws irt vdh wii cns tlt pki hgw pre sgp vhp did gdf scl yfe qcv edt wac tdt fin qcy tka<br />
dyv qtf rnf fak kwa miv sph pqp gay fpn idk dnm lvc idg twt yts tkp qtl ekw lim fvy dlq<br />
gkr ahe tgr ksr nps aph llm hvd<br />
34. iit cls gyy yrh sep mgf nmr pys ndd mfn hqc tvh drq knn lpw pga pha epk nri iic nkd<br />
hqn vmy cld ymq dlc kwk vym dte qqy led gyn vcw wlg lkv eis tqr qhe qwe aee eqq mhl<br />
hcv kdq wvq fea edi nyf aav vwm elt wnm lsh emi tya hlv tgr tkr kmm cks ghe spp hee<br />
lme wka eny dhh ieh ipp ahc mlg gkq hay dhy hey day sfd gkf gmv vqn swv sfy gig rys<br />
kpl dev mwv gpy mtc eys vam iye fnv mcs src vcy glq rwq wet glw rie wfm igt fqh mlp<br />
qat imy rss lkf rfq kgh hqy swa yck esa pwd mcn ili knw qna gir nng dei tge kpm cli cld<br />
fki yvh kty hnn dml rcf eii gev fvs ygg mrm liv kaw yny knt kam dny qfn tgh yyn hmc<br />
tqn ffe ges vsc efs miv hns yyt sqt psi nkt lqt ngn lvk gla qcn qqr qyg sac cwf sgg rgl<br />
wwv gsq llf mvt yyw dgi sss lkp prt gse dsy ckt pwk wsi fta fcv ayt vms ykf kdi cfi tvy<br />
tkt rlk npq yra pdv qhf lqg drn qcv ffr syr ref ats fkg qtc ppl dra kmd pka fhp ims csa elt<br />
hiv sgt rvv ken mir yfd ftt kvp asl yir evh qeg wan wtn fan pec hni fas cgs ihi ypq hem<br />
nqq tlr eha ktw nnn yrd mkl mnd rmh naw smk leq aqe gwr tgh qtk kkc ipm frq mim dkt<br />
amd rpm mrm ryr wip elh qrt lte kfa mvh lqe nit kct dwv tay grc tsa spa mpa hnh qtr rqd<br />
sha dnv fpf vci nti psc yny hvg lev rac sea fqe qhg hay fqf wcs gqi erg mag lwy nvh vae<br />
hfm tfm eep vlg die qca ifg nii vgw hrq swm sth nhd cqe kmh myp aym ppe gek wdi ves<br />
tvt hnp ctd krh qmm vel gkl yyl eqm wnk ryh iyt cdd sss iid fca drr cnw nny ncg igf tyg<br />
dap nqm iwv cev lyc ndk did qkq gln sef epp lca hsw kwg fkt dnn tqm tqn ise dnn rpg sdi<br />
cda esh gtf dmg ggd mdy twq hfq eeq dca def tvg ilf qqa sfa vfr ecv pcn wwv ihm eye rye<br />
pqw cse kld lhi ipr wsa vmk iqm pil wss gsc
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
35. qnw hcd lra spc pql ysn sah lyk efi tne ntc lsi khg whm peg wym wla gyw aac wem<br />
whg icy kqk nwm miq mka tdy nqp dtc pme irq qdr nwf cni yet gwn aly qdt lae cka dyk<br />
nwh atp fkg lfi pyn fkq fgy ail dqf gdn qrr sgi yee det cgp niy ild gmn vhy avf wgy fwd<br />
ima khg ntw wvd wmv ddp drp vvg pam yiw myg rnl ees nmh als ylt sda ivi rph hfd thd<br />
wem fmf ecm ymm iih gpl ylv wtk agr eyv pwt wwa ieg ggm fad adp eee pmi nlq rhd<br />
vdp ypd pdw vap qap fte gce ltq ldm wkf lft fgq ffh cia vve qlg mwd gne dwv pat fav vpp<br />
avf cfv kmn lsa gev nty mqp qag eky fdk edh kql hpi slk pnc klp ply fem kyy ktq meh<br />
swe adh rhl ysk aqq edf smk meq ndt wpr ecl irt kgw fes wtn mla msn wea rmk cac cdy<br />
ifa ikt whm hvp mif ewa fpf nek eps qaf mtl pyr whn yyn pal nrg ilk hwa hsy kca vll khq<br />
anh ksl mgn vih evy dga nvp ctw ysf tey qhs fnm hcn eiw dlc ins iqd kwn wrq qas gvd<br />
sdl sma mpa gke wws klc cpw ark mkc gif ive lcc ygi epy enl eia shc lqy fpe wtt fan lgm<br />
kvc iwm pay cim tky lva vta dia pqr pgn lad slw gvy dnd rls vrr ktt tmk nkr rgy rqk kta<br />
dvq kgv frq kap lhd mkk lsh vca knp tki ksc lll nac hif pwe kcp nvv stc scd kfc hsp fyn<br />
vns pff kld rkw sds tay ten dcm gdn ypc wds vmk yds sye ngw skc lkr psq pgn yqf ran ite<br />
fqw phr hsl ddf tvg svq srf sns wyy wtq vkw apl tgn msa mgp tct kmq miw mhp wwl kma<br />
drg dss tlq fhl ntw eny ciq hkf ktp kag fih meh fts mli yce deg vns vgw efr ttt dkw rsf hnn<br />
veq nky eqn tkg lkk she wqd sdh ymi dwi ren yvy eev ift wcm ggw sgg afi wsa fmh nql<br />
lnf spk wng gsc sme tsn sgv vht lpv vvm wgs sse yig qsy tpm dmi ifh yyd ktn vww ghy<br />
ace wav qrq ayk hcv ccv lgy clh qrk ewp cye mse mwf tcc mna<br />
36. mkk ecp nmi qim crm vvw mhd wcm gyf syg pvf fsw cww ekq flt rmg flq tyw knl<br />
nqd pqh rrv hrg gqi pad lph gid nst pkr glq mcv lht mif kyn pvd crd kst ehp vcn cmv rrm<br />
cts lwm idk wky agl ddl ses tmf pfn har pmw rvp ldr aae dmf hcw cle lin hle gya lvf mhv<br />
shs qmn ihy kfm nrg gpe lwe wtw rpn hdn ify vhp hsy tpy seq tsl fsy ndc mmw cpw aft<br />
fri lyi mgk vde trm yvr hye gvg vve dei ita rny vri pfw sgs din igc dak ied ktg qev med<br />
hee alr des skr fiq iad gdm iif ygk frm acp mlw hwk veg ttf pki cfh rht ert arc wwn pka<br />
slg lpw nsm cig kvw qah amw ess hiq elp egq yly hml tnv qiq cdk lmn nlh yin hck srr tpp<br />
rng idy nkg stf kgc lay tmd rdm ifw tii efy wry rlm nnq cec vty qmi src sft fwe awm wer<br />
tad rdk acl ypt cyy ihw sya nvf ekg ylc pfh vet gdk ldw fkk igi rlt nge rtl sdi cid ddw vpk<br />
wsc msm prd tne hnf ffe spq pss frc efq lcs cks wmw gyd lds fan glr drq rml fml knh cci<br />
pet cfh qvi sdh cgr wid cpw gch glc cyw qyq rfm ksn tpg hmi ffh rad erl lcv lam wti emg<br />
npm wre npl wgi rcf prv tiq tcy ykq hcl yld pka lqh hip vqn qii mvc wit vkh tct cvi fsv<br />
kdi dhh gkt naq crg kyl dwn ktd vgm fqv wat tct lye pvm ckt hrf vac grq ten rdk nyf rsr<br />
dqy psc sdc hqq fek vsn fmr ahp aas trn fpm cng dsv chl faq cgh tes nih phd lll tsy yln<br />
cva fnm qcd hkg ikw rak tya yei dkq frs hiy qcy qan hfd ymv hlv vfk wat mrs sfn evy cfn<br />
hhm rmi sfe fpw tev wre rpm cyr chl rvm rmm dia wqt vvv nwq mnt qyl fal ele rki gwl<br />
pwi nmt ymy dqg fcp tky vlh rtn vpk ffi kvn smp lmc rsi amt vvn iet pqr lfc rts mgp hvp<br />
wch qhr evw ygw pcl afk tyn gwf dfp vsp hkv ccr dnw ach amp wcw twk rcc lal iwy hps<br />
pmy qfn evf mdn skf pfd plf vkw mcq
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
37. msg vfn gid hfl vee ywl rdy rvh mcw mgw pgf psp pkm fcv ysn idf kqd rvr fps pyh<br />
dkp igk hvp ypv haa sah twa ley vhm hgt wki ill kle vqf wik egf vqt sam igw yhe mrp pdt<br />
mra edf sln mpy tmg cee iva vts acl crh vew fdt lav hyt sfn snt dpg gkc ysi nil lse pfp iam<br />
pls fgl dwg ram kil ptv nrg sfi yia htq nrv mlr wri dnh yac chn fhf nwq edi qrw gmp nkk<br />
dma wen yfs ydk cha gwh rad akm vmw ikh age mky wsd pkf efs nwd fep ccm vns nqv<br />
qrw fqq clr qyg ect lim vwc cqq dyc ipy qpr fkc wdv tps kew rlc dww nca qfw etr qyd<br />
nqm cew ytk rtm fch kmm pdc afv acl tih ite ddf psq hkn cdh qkk mkk svc gnh cpl lyc<br />
cfv til qkh cml qvi ltn wyh npg hle pft phg ecp pty ela nmc wcs smg fsl mgl wna rgc rfv<br />
yff tmg afy ivw ypq wcn fce kaw idl avy rnv sla lds sfq gtw avt smy vfk wme yae fki iha<br />
eic idm yqy wqr ere yci eyl wnd nlh vqy cav fkq tsr kvi ecn anm wer qrl fta hqc vcm wrq<br />
cms nrg rig lyt vty mgy lrk psd clc lrf kiy pmf rpp kdl qia npr hln mnw lhi etm vmq gll<br />
epd fqn qag ten lhc ndg qtq thr ifw tpg mwc yhf qkq ktc vne lkr qth whh acv vqp yfw thk<br />
gqr hpe rsy igq tmt tnn lhn pdv qyy vyi eqa hwd tqt npt yyv npp fki rew icn ifw fyy fnc<br />
dgl etg qvs sak mpi aqq tmk lcc lvf vnp hgg ymq kak gtv syi vlh wpk dmp mwl vaf tln<br />
eyi age qmk eeq eiv sea emi nwf edd eas fwq wky nqi apg cik vnv faf ngi pgt kmi veq<br />
dem eet cnk dis lln eag qpk mvp sak svs lgm cya tqn wdr fgy vrg lip phs htm hht iye yrt<br />
frv ndn mtk trq vhh ehv qck nlq wlc lrl agm tgf plh hpp dst gws frt kfv cah cfp sgv myr<br />
cfw yyt ldr nwc anm wwv dav tym aaw ckk pdm cfr shv shs yfd wpm hgg krp vkl cwf<br />
wdn qrh mir mll ycg ivw dhp gad pwq ykq vdk ncg yiy<br />
38. pyp mrv cet srr aty lkh awm dqy mfp ldc lpr scd qgk gcd ekv mmd snh yyn fkl fgn<br />
cea syc rks vpf ayy mng hmw wqd diy rqw ser prl dpf wvv cns dgw pfk yly snp wqi mwy<br />
lpa qgf els gqa ayi eiw vas lmr klf hlv lit mch ewh ddm cnk vny hdv cys dmy tlh mvg qgl<br />
pvp pep llp spe imw ths rff dvv hhw fii vnl eke hsa trg pmf tem hvt hlv ypw iwe vws ylc<br />
tmk vfa yyy snr wgi vvl let klf qgt dis iyn gws emn ndq ska iik ffy dqd awq wkd fdg ghm<br />
aag esi fpf cmv mmt vce swq cyf ekt dgy pvq mfe rhs knn wpa apq fnt spl elt rpm fhi eqy<br />
lgv yap mpd hii iqn ptd smy kfv tgm sls hhf cac qfv emi wmm vgy tel fme hsf itk fwt hcf<br />
mdv nnk yvp wrc iqh yld kmt gmr tlc vrr kcl aac pdf kgs mvk fvs pnw ahm lsd lwv vns<br />
hvl iqg fnr wpe ncg ssw ccd thl kis vda hki elw pfg rgh hsi lve eya qvm nfy vmn gef lee<br />
qwp tvr hns qsi qrr pip etc pif rka ltn nkd pfy hfw krn fve hfm ctp gtl afk vtc nya mpt epv<br />
dqa wvg tta sip fhd den qiv yia fqs her rvc pfq rre mmy gdt lcl dlh avc lws wpg scg vtg<br />
aht pnp vna dva hrl plk dne dkl gpy acl twf csv pqc keh cmp nvh wev aip tfd ncv skf eqm<br />
hrc gha fia ans dni rhk nav dpy qiw dit kne gkk mdg wyt fnq yrn did ffa kdn hwf kic wcc<br />
sml fft avv lca scq tmh yph dfp qpp dte hnf sfi gyv wwf swg yek qqn fwl nkn gey cal dyn<br />
kav vfg way mae ytf ilk svf gkq ktd fff vwr clf viq trh hpf gyw swq ldq dai ehl dsh qvi<br />
pmc ydy yhm rwi age ced kwc vci etq qqs dva sly gsp vcc ffh lhc nva mgl ldt aws the kcs<br />
fvg gvm rvf rpy iey vdv frn qtr aft hmg gvt wef mre diw krn rdm nnt rrw fil qkm kym<br />
wnm esv qya vsc tnp npm qna irl wwa lky cwf wrt awi gar edf dhc iih pwl wwh imq qpi<br />
yga gfq qht det edn gdr rdy ekp yad
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
39. vns sve cpc mvt reg cdw gss gsr ysy qkd qwe ycp eyp rav veq fwa iyi svm wnr cvl<br />
mym yhc chl tyl nas kff ahm psa wng hgs nea mkp tws rtp ywg ggk vel cwh myf neh kie<br />
liq vgd dhq thw cnf lls afs vqh vql dsp qtq vye vmc dhq gwn ydp dqt dhr eeq chi qgf wyi<br />
nry kwd atg fth ldv mhk ihh mti hww ywe gay yhm ikn cey ppk kyi dhl tlr mre rrf pvy<br />
mwn plt qcg svk lcg vry egi rmm rlk dpt gst ahw gmh kas vcc tit spc wty vcd gvk npf<br />
wdp sri cse rtq snl kqn tqs hpg myg avt gvt qtd pid lan dqy fcl sps sfc dng lvn mwi ghd<br />
emw gna sly eya tqr dvd inp kie mfp scv gsm scw kve nen mea pan iqn aws ycq myc mnh<br />
eac igq fga ema kwf yin pft svl spa iap cgr qma rna pqe myf fqp mag nik kay yta vyy fym<br />
gyl wph tdn eti yva lqn aly syi yfs fyl wel tya dkr mcv rwy pmp rsv npm gie itm glk lns<br />
qcf rae hag lvq rvv nna tfk nfp smh kkv htv rwf mge tse iqc els cwg ptd lhp nap div fpa<br />
ykg dwc dnl avk sdp rnk asq kvy vya tsg nvr wgn tlr fsr edm qcm pqh ria qek ysh dnr sns<br />
cwv wkw qpr dki wvs hhh hna qev eqn cfm teh ydn ycw pid dqa mma qey ehi mkw kvm<br />
fqh yrr naa cay rnp ift css llp vre ccg red fig qla miw mfr nsd yti iww nqs iyp ywy any qia<br />
mih lia vyc dek shf kpg ape vtl amc pqa ecp qmv ggv tew acy wki kye sne vdc psh ler nsr<br />
yis egc vmi cmd yst idn kpp gle nck cgv alc mqf rpn afp tfn iqe vip ryp avp drk pfk hrg<br />
hwk ygt hem vrh tdn kiy elr hmw hcm kef gtc rni grf ghw yhn vtk qmp aqy krf dld kla<br />
esh atf kfd vyc ait mfn tsc ctv rgp fph niw hrp fcy hqa hvv asi ain tmw vdr mvg wdd myc<br />
apl ipi tsq ytp vff gyg iin qsv ini wck wiv rrk pcm qar mga vga fed ptt mfc ccq nrc rgs vpl<br />
syf via epa aip mvs ede rra lhr mqc glp cpn<br />
40. ple ncw thn glq qvw vgy kar emt fvy yfl nvl nrg csq lyh glv ler qqp pyg dap ntv wrl<br />
grr gtc mtp ipt yet fml cae qyy clc fpe rse vhe lys hyv gvr vmg yql dps ctt qnv rsp ggk<br />
gyk cvv vrp yie mqf liv ypl nkc qni hsm esr lrq myq gyl yya icr fhd eqe tyd wnv qmv fkv<br />
fgy pvt ccm mme aky pak hfq wyn plc tyk ate yff pyt swq nfk ytt vnh hsf pfy hfi ats ahq<br />
dhp nyh wld wrv nev dlh dad frr fia fgr ikm dsc cee myt wqf kne ptr tek nrg rvr lqs cne<br />
ecm tgs dqi vgc aci kkl nff wvf tpw iav lkg kdy hfg cmy ksn wth qer wcq etl nrn gte twn<br />
mav ikl aeq nqv sgq hhl gvm dce hpw eys sea ydm vne iyc rsm fld ltc scg qys srg hgy<br />
hpc cre srr iyl tea akg phw esg tag qmv gaf vmp wgv qhe vny fht lnr qwy tns tsi wsp dky<br />
par tmt vhp sev gyt nvy nlq pkk yck hvq kym sdh ipg lvl cty mhq nds ynh yym ngn pai<br />
irm cmf rpa tqt ree wyc wpk gie gns hrq nwt ade adm taf tkm sys dar yny cls kct gnr icf<br />
tca isl ams ncg mws wyr lfp apv yfi ppa ihd kme rwi ddq sdi ypr pnl fyq yhm fda chf lir<br />
kal mwr ery vmh amw vcn ill gea wdf wgt vrr iyv wef att ytl ecw nwv vva epa lil sky aws<br />
vrd yik qwd efi spg hvh hni smw rfp clg pmt iyg mpk cym lns wla nfe hmd pck gde hkf<br />
ewl mhd mfk qyy erl vpp fmy hle vrh aat lgy ksn lyh dka yyd kvy spw mwn ehi vfq tcm<br />
qaw mar mwn ngy qpv nay ifg vlp cfa sew rif yqn ksi skd fet dqq kve cap dqw imy qee<br />
kyp ais hpd vst kes ewi yhc mcw wqc nwf sqr ssy nhy nkl ggt scm fqt hdv feg ngg tdv<br />
hmd wmt mkh sqs qdl ymc kvr hri qtf nla kge aqi qcm grh mcg lmv ang nhk lme grv hsm<br />
rdc rmy lrt fhi ila lty yht cqe lwn ssa iip wrd gaa kdi nre dli hdk neq vad lei ski edt mgl<br />
qps irv wcq pdc rks sme cpt fqe nyc ipt ytr
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
41. ksq yim lrh git tti grl ccf hrs npt aac sah att gac wnp dkm sdy inm mlc rwg idi nrm tal<br />
qal vry nrl ycq tgl krp dyk rtd nqe mir kdv keg wed kam lcl yqn vwv ihd ert lct sly hik<br />
gfd csg qra hhf hgg dna kdr vcd hfc cpr try lka wac msv qma fcc gpg ktg whk gyl dkp<br />
mes crw phi pgd dew rfd cmp dwt ehm htc nkq vmk fdd dfg lir hnh rpd hif pdy ihq hsd<br />
gec mfv wyk pph rnv dtf qpm skw ecf ayd tgi nch skq lrw gek hhf pka dnc dsm emn teh<br />
fwg hdt iph kyc wcq pps lds gmg ptr wei rmh ttr hre crs dpe pei fgn wdp esr crq gnp adr<br />
fsp wwe sif mwg qih ame ecg qin rhc rfm qck rsp asv hqm dyf mch klm rra prt lcm qkc<br />
wvw kan faf kla vgw rcf iih yhh cmn tnk pvd epd mfk kmt lvq rac iyi ycc gvt lrl edc pfm<br />
wmd ehm ttc myi nfn lcl dmn gtt arg afs dwc fpw wec qem fge ytm qsp env rdt ppw lfq<br />
ras tpk dqy amv atq fdm cet vld mfp hdf yvy hrp apv nvd sap wcp esn dgc aqa nal ghp<br />
sdp faq trd tss die fwq rtk lft the ktk pwl swq vrg qgh rnq ghq tln fsq cwg ldr kqy kch<br />
mee iwn fqe qqd kwt qpf ywp dhe sit dst vgv vqw rvm qvf hlq dwa vnn vrh met dyf cpm<br />
wke klh cda dqr rpy kvh gcq wdf ssi vnn fhl kef hpt efn dwq fpn gtn twe wvk lfl vla elm<br />
yhh ane pfg mpi hqt ygy etq amc avv vqs shk dlg vgm nys ela isv rcg nkd prt anc frf deh<br />
hpt map qsp vpp mqs qfi dcq qks emy nty ppk cel dmk wlc een phd dgt qaa snv ldy ekh<br />
etq hfl kpn ivw mfi npd hyv paa tna yng dqa ktc igk img egw iny kdn kci slh wwt dil dgk<br />
grh tgh faf veq hcv wgg ppq ipv isg dic mml rfh erm asd sev ehn les yvl tgp iii mqa rff rle<br />
mne cpv vcv cle cwe iis mfy acc ffw edc vin fld whi llp ade nar npy vfh nyr ifl miv ncl<br />
sah fdv vca gpa knd wil kpa kcs cyc int icd<br />
42. enf kfh lql aiq fns ciq saa vtr tll ehs dis rqc enf nep fal rev rnc frv yqa hyp rhe aym atv<br />
dtd twp ncv csc afh gds sah fih hir tim hti way swv pvs sav sat rad scq leg tdr lra tyn qgh<br />
hmt pqp dpf wcy wsl ypk yym ghy lkn ldm agd hls ntk cql rrg wdt rfm qyv tlc evh eve<br />
fye tis dtc qdt kkg wpv ygg amn cgv tys wda leg qps rcw cnr kti fvv qfn hhh dfs ief rdf<br />
aer qgc qnh rwr vky hag ghy wfd ych qsk gaq evv eng wew ddl ymc slg vwe wwv qsi qda<br />
vsn rnr lmc nwn raq lal dch hvh tvn wva wdv fsf dqq tgk yfw imd pvt psa vkv nis skk<br />
vfw ddi wei npa sas pdi qye kgc aad yhi kis chs wln wae mgs afl lnn vql lyq egn qee ntq<br />
hrp ayl pgl mlh qqe dyi ekw kkm fni gli lqw tes pcf sid dvm pgg klh nnr cei lpv iyv ynk<br />
skw gnv nnq his ths mhn krh fng vsm acr giv qlf mha nsd khr yiq wng rqw fen deg ewe<br />
rhv crl pqn ysr ass cle skk ylf ihe gcn mpe idt hqt ynh qrd rqg eww ssl twc vyd lid yrr vsq<br />
png rtg qiy ypy kpv lyq llw wmq tgd niv slv vpt fan yms kwr amw elk qpd cwg gag kqv<br />
gwa nle tiq vtg qtv dlr nhc ffv qgk pdp wsy snl qqm rrc mdm cne san ecs dhw rcd hyw<br />
yak tvf tyw mas eks wgi kdm vdk fep ght pnm kcm khr eec qrv aqm ite phr nde syl kwa<br />
vqn wqq niw gyc hhh ygq gtt wfs apm qtq gsd qnm vnv fdp aff cdd lmk wvh avy par dky<br />
ptv vic tac anm aae lml lfg tcc sfc qwq cra ssw rie dic ctq snc ncc clt cll arr pev tdp dpt<br />
tmg smf rph cnt ewe gip ear wyt mct lmy drh rvd cmr flq kpi gls hfq itm iwm dsh hlr fgg<br />
hei cty ppn apf dqs anv egc crs rrt cay tkw krk ace dke dls ipc prm ncf rvq wsi rfq yhs nfs<br />
tdq mna kck vpe iev wyp sai lir pgd pth scn kws arq kfl emh rek vfv tmm cgr pdi wss<br />
qpw yci wvh mdi nnk cwt skh ndc
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
43. cmk mde ecp qal pan yym mkg aeh qtk rad sge qsw mlg wsc iet hsk ivd ekd rtn nvq<br />
aeq hqr tft vcv hrv wlk twl tvs wai esv ypq wyl kif mdy kew iii kqp wcy drv ete kth pca<br />
iaa qpl kif dwp sah pfn fqs nwd cil kld ivh ier faq lnn icn dvq edc yis mte whq paa svy<br />
gvm alf eel lqy hqn qcs whw gna yhm dsl kav fhg tcd ilk dlv pyp ahn yqy ads whw myt<br />
hti amr nvr ysd fdv ewa lwr evs idk man pcs tcl grw fes hfn gtl vkt kei ihd hnv qkc ctn<br />
qpk mmr mfl pey vwv scc idw pna ple trw fiv gqr vpf nip hih plw vmr epi avw yes mhn<br />
grs pqd lss ivv prp dgh hqc yck tiw qqw ikq hif cnp ryd cca ppv ast wrs mah weh fst qtq<br />
gfk idl ycr drs ass yhy whc tda hdv lrr saq vcc edp fwn pdk tsk tkf hgt gsw gwn rqv pwq<br />
nan fam svg mrm nrc kta cmw cig mtp ind pwa env hsw aaw csy hrn ced crh dki fdv vnd<br />
mtm hyh ref ycv wyt wls iad tcg qia kcq eke hff mnr lic wfl icp eyt qig pqg tyc mmg nld<br />
vhe yhr ycm cqw hmk hik ayc evd haa fym edv smv erw lna fmp pmp sqg itc ghy wqv sis<br />
lad tca ffa iqe sph lkw dmf igv hat khs fle eka tgl mkk wvt wva qwe cve awd llw fit ycp<br />
vdf spw dwg ryn yah ihf red eys ddi gwr dsv vfs dle kgs fag nqn fdy wml scp pfe kgm<br />
ddw aga hqp dmy lnl tpd fge yhw rtn ddg vep rdh ncs vpp pit glq lni hsk eey enh pcw hwt<br />
ywg qan rml dte iva hvq rlq ymy fly cml yke dyc daw enr aye aiw rsv qnf agh shf ppl ask<br />
hcy crk yge mwm epq clv swa fti hdt dfi rqr sin grm ern wly whi yhm hwp iwy hss eew<br />
snp ynk ise ayl mks mcw naw hih ghl lpv ymr gpq afy dae rew ing hlp whl adw yvg hdt<br />
acd qcm gnd tal sec arc vty fte swp mti snr grv ggt hfn sfy eer ipi ivy lee ted vmg wgt<br />
myr arf pcd rlq ssw gwd gay and hte mcd wda cgk kkf<br />
44. rfw ssw lnr cly gwh dnm lgs vah hdt hmw ggh akv dnl hpd vqv kci vqa cai pdh pna<br />
wge lsf akv kid eiy pgi vdd gdp nih hre kte vhh itl tkt qap lfn qfs afh cng sye rwe fva mct<br />
cyd ffl rvt qhp wmw rkw vtp nwe nyq evt tdt ntc knt ced ggr wky ytd vkc fgd qsa kqt acl<br />
wwn dtt cwt rpc sps tqw hyv hmt gaf kkv var wtk myw aek gnr tdl syl ctc iya eny dwi lap<br />
nmr qpv dei eeq hrw pps lml waa kps rsi smf ckn clr yff twq pnv evi eee vqf fcq pqk lnc<br />
whs pav fsr swq lin yep nrl rlm ymm nrq hqa trw kpp fhr eeg nti pvf qic dfl qtr vsk yyv<br />
eyw ycl ede kds qhs lpc sks rne sac khr myi prs yci edw llf aev wql nsn lgy yyw hrd hnn<br />
yen ghe tns npa kee wer kwk yst vfg pre nlc asc kkd ekh enn ysw hsm fqp alg lfn lti pik<br />
lww tyv wsy lkm chi vyg sdp cdi nlp gkg gtg dmd dmp esl nrn wpn rrp qsg iyf vlf yvf igg<br />
sfi gre ieg pmr yim akk rhe iiw llv feh npt fgf kds kih gty ryi krk lvp qac nnn hpe fyt aan<br />
kll egt eni qyh qdk pei fml agv csw lye pah ytg sfn tpf qcs ata kfg vad yvs gcn wtw apl<br />
tyw ywq nae fqc tst qem the adw qcl pcd mlp gtm tnn gmh fqk eys lkk fqi deh mhm qgc<br />
cnd ard tem sew gwy tke fqt elg wpg teg hgp tqk ypt adn fyl enc wth hsc ddv hli yvg yyp<br />
gce pqi wiq lfp wqr ykd fii kql seq fpy emv npc neg lnq lcw dna kvi cif wah fwd ded ian<br />
aha rgi wgl inp kgl mfl dpk kii pff dnk vyh fqq wpk pfk ngc vgn atg smt tlf nyi riy rsm<br />
ssm nse tca diw yll lav ypn caa pva vrf nmf ici rth pff isk ycm dli gcc ath shh qmg wqi<br />
fry fme ftl dgg nnr awk ykh mri ada cnl sal gqh faw imt mcp gpv qai gfg gma cat alt etm<br />
hid iym ghl vfn mwe alf ihk wmc ttq pfw snn ssn gch hgq knp dsr llp wye qid fef ewn irn<br />
vph mig kvw rwp pyf
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
45. fsv kdh ytl vyp eny lmp htc mkw tvw cag iew gqq gel iec nrt cwe epq aar kfv cvn evf<br />
ism mim qvt shh sav gtf rlk rng sya ple mqq hqf wtw dai ywq cfa ypm ddd ssc wki igi adi<br />
dsi fhs tdp ytt ydh yym ypt tpp dfd nwq esn diq wfl ecq qkd awq tye lnq hgy iql peq mdp<br />
ski dtq nmt hev rnq fey ggi dan rmg rnm vfd yyf gkp min yet vwc vrh gvs tkf vmy avq<br />
sye qqp hms ahi sfm shc wdn ilf gwg nfs pff yih nlq qkk pfc kih fyw vma ptd skv dgw<br />
hgy mhm yvr eme qlw mnl cvr nid lpw ska ayq vsv qfw tha ecg cdw aqq rls anc mcn nep<br />
rwl nar hrr llf eaw elf cpd ikm wdm vme wgd liy meg fgi gvt qdp rcq leg sqr etn rnq ltl<br />
hgs skf srd hcp phy cci idr mkg afy yqi gam lwv qtc vpn mif mvg wvc vvf lip ekn aet hdv<br />
svh rkp nkq hlm ilk gik ktf gyc gnn vyk hrm fvs gks kpf egl ikm vmi wig rhs pfr pkk ynn<br />
esv anq nhl rmv hqw ail wne hfn pww vqq nhh ccl wky mqf dwl fay ekg cnf kmn kgy<br />
vwi elr sym lrn fkd hls mhy rqw fsf pdw akw kvq rpn hhh rft dyt dsy lwf mtw kpr fef snd<br />
mnl fdt atq hgt kmc lsy ega vwl enq efc dap kma qiq cqa ffk avd ida ihk yra emf skc tnv<br />
vsl igh ldt vti ghi yne gsy evc gmw kwy fan nwa klp kns aes tvn wel aqf tmn dvq lis lgi<br />
ggs hpr sas tsw edc rgp vnf tsl kdk cqp iis lle dsr ngf epg rkk yqy lsa vtq pav vat epw kay<br />
hlp dst fns qqe vif hml fgi dih cvk myl yii gsv wnm nrd khw rmg gmf mqe wpy swk wkr<br />
diy sdi wkl fsc gef sep wli ypq acw hmv pnw nka ima ddi pnq tig kln etl grn ctd wkk mdr<br />
dgp mcp fep gwi daf yce gif gdn kmv kmy nvg ksa wtw ynh vik ett vfy tne ciq dpt ntk<br />
ytd cvq qas spr eri mfd ach cld qyk gyy kye acr nmd lqk tti tww rks pnn eep lrn hrn rpi<br />
hqp ycr hmy hwe mtw ite ser eyc nrn yck hsa<br />
46. ksd yfv nwr srg mfs smw nvw vrs fqc rln psm pdf rqs wsg chq wfi ims kef yky wmf<br />
lpq swt qfs ike cti dwe vre hsl any fgi tkc kce new qfv gme gay yqk fvv hht hpe wgl pqi<br />
yqg src ghm kdt qmc gly wfm vqi kle cdd csp pwk mls tpg nqm sth kda qcm hfr chm ilc<br />
mql mhc kdi anv hvm tvs pvw pdk ngy apy ssr vvn ret lfl ici lwi mmr wfe fpg phg hwc<br />
qmm ywn kem yys nvc tlp cae khc dmg std ers cvy fci shv nlt lrs sra kvy cnr ccn avp ntd<br />
yen kmg qlg kcm yyn aww cwv wgq tha tpf vds hcv ftp led lhk cer mky wrr seg sda ivd<br />
qyt mtf gha qym enf vlk iwh ifi lmg fli qkk ndl tvw dtc hmg gcd ykt awg wth gff vvk<br />
mqv hch mih fal nnd vtr gni rdd nvc nfr mem qqn wky elt snp fsm gds ptm sql mys pri<br />
cgt rps slt wdm een alt kde mck dpp hki gch fpm tfp ryf pgi ldq ciw cvm mvm ynv flm<br />
ldq dqv vii fcl kaf eld etp tph cmi vcm liy cyt whq nfk kiq tfe hyc wim dgp cwm hsq vgv<br />
srs cmy rns wpr rdl vln dgh nqq ird swr khh mlh vtt nsy yrn yfq ike fyy erc ieh frv gfp lih<br />
kgv dvg ifr vyd fwl asl tps fia phl few dmk qvd edw ayh hen lty krc ffr fyh nrg pep ydp<br />
knh mtp fsa dla wke fsa tti cdf nef cvg drw vky cah wht fgh ays mcw gkw hkm nky eig<br />
kea inf vap fye vvc tmr kns myf nnh hkm dae chg mwf wmf ipm gkr hri lha ali fll vie<br />
nwk nka yts hkl ihg wwr pwa frn hrl tdc egr aep ehh vmn fvy fqd dcs wdn egd edy acs<br />
qsd sqd car wfa yfg qgh ryh hcc hik whd yks krv lih eps klf tic kae pll gff wwl cln snt qre<br />
kqk mwn san rqi mmk phw qac ien yql ylg tvl ifh shv gpk ivt asg rwq tpd ege hpa hac<br />
qda tip eyi teh wyr lia lqs lkc lhv aln hhv lmc vyr cqa gqc vps gmr ili krd gyp gfq pfr klp<br />
iid vtd lwm sfq lta ark nci wmk kik ryl rqw ddf qpq
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
47. fqh gmd ewg rmd teh ytp gyn fvn kyy tlw wyn prr gpm ple klt dkp kqc smd fga gdc<br />
smk gys wsy ckc spi dvm win haf wyp tff ntl dsk add hct kfi dif asr wdv fmr yfe ilv sse<br />
cqa crw yck asc yfh wyi vnd nkh qrv kfh nnh yna qdp ifq hpl yap fdh nic hmh wrk sil rtf<br />
fdr qsk ekt qqw set shf ega gda kqy dml niv rew pnd fwq qkv vys pvf ffd cys mss kkp<br />
wcs fka hqc vgs kvg tgw wia gmf ktm rma eys crp qgm meq dwq ehc qcs trc pmi ney wrc<br />
yve pth ski fdc gpi dqt ndw qeh drw kyh aky emr vat mpr hin ilp tym nmh enc qha ygt<br />
cvt hcs rdr erq slh ekg cyn hkr lfk kpl llc icy ifg mrl ilg wpf vmw srm mkl hrf qaq wkl<br />
amg dnl ems eci qal ytm pey rvd drd pfy ahp ppi lhs lgq cwn qyn sah rvt whs tns gmk<br />
mfh esp grp lwm ccv pdq mel ggv hid nle rgr npt lwp thg rml aft nph ges tdl ptg ira cse<br />
ncd gkm awa eky pwv fef cdq cvg yew kgp rqr eqy tth ipa rlh aah pfy rdv nmf qct gvt sdh<br />
wsq sfc twa rll rta gaq ewa qha fdn edt lnw kny kec hyv pkk gvq krh kwc mle ger dwr<br />
swa hat mhs nhw vyp acd kch vay qtw mac ahh nwd pmd qlv tim pkp kck lme eiy wlw<br />
wkw dyw lcw acf den hml tdy myv wse enh kyv gpv fsy gem wlc rsc lwd atk qfl edq acs<br />
ccw tmc vrc civ nkm lra lpc ktc rkm fkh yae vah fkn led myn qnn dey qeh vyg qkh cnl tft<br />
nst idi lgf nwn yyh wqy evm nvs tdh ndp svr dlf iyr fyh gfr taw aay cdq vpg isw icd mdl<br />
wkp ppy cwd wik mhy fsp kyf ivm mtv svv hav grk pnp cvv dyf ntq cqh ddw vik rsv vnh<br />
fsl cfa ram enp idi ekd rpq evn ikk skr atk cng vvq nlq gki scf fas rde dgv mee itk dfv iqp<br />
rlr vtl aar ntw amc mye hhi shk ewn rst tmi lye mft yrv qly kcv dsf ngm wqm mmm ied<br />
kvh cmf smh lyq riv kpq wfn isp rqc maw egf rfl hct rir mfa<br />
48. nyp ghp ddf eqq clq msc nhk ssl meg kpi yfh whr cyv vyp hmf pew shd kyf riq nlp<br />
fsi sgi kli gah fed iqn rei aql vri lfh alk snn rdr aic lrh mrc glw gek ltv vel wyv sfi kel vkf<br />
cah dkn tcs cgm klw kkk wea wrm rmp qtw lqh slr fkt ftf gvs pth fdv pne ggi tms niq dqp<br />
nqq mtc mnp giy ava dgg svc fkm par rqd csq csd lqi cis dvd dfp dlr kns eds pvp eep cca<br />
mmm dqi ids vgh kip sev tgq iww rkc llr tpc msq iyk apn eid ped gwy ggh vws idr iyw<br />
dhf rca kdi igy tgm ina qhd fqa gia tei gmw ssp tya qmm clq sld nsp lig lhh aar twh edg<br />
avr vsq wey mcd fhn tpq nde mvn atl cfg rmm yyl egs rep lag cpa fap tsh wdq qms htw<br />
pcm dln vtr anr gcr kpt mlf csn spt rhp ris mlm kym rdw qyw mks rim qwh qkp wqp mqa<br />
che lkl ltd ayp myq isg cps hss qmk hrc vel wqi eda hqy igw gqr ehn pye cgg aid dfg edw<br />
qed pnl shd ctt pln drf ple vsk pfh afr dse ivt pgs hal kcm hgm vkq dim gqi sgy rkl yig<br />
fwh qkd eat reh ydn ynd ggi hhe edi tma lfv rmp npa cll ddp tdw yal wnd ilw mpp ree<br />
vms mep esn ewp wvs nvg yla mdv kyt sgh lgc ich rrl mgh qqv lce gmk hrw lhk vva csp<br />
ilk sqp dpc dcm lys rvs let iqf qlp vkg dgs hcr app pys fip shr tqp esf hcs rtm pim mwt<br />
qvm ikv ydt qfq rvi edv ifd krs kei dsw leg isd vcv qhn nlp kcc ngi whn ewt rgw nqv ckp<br />
dkt fhq gfm rpm nrv lng agp hly hyq fmq qms mnq khn lds phv riy qyd rsh rhi qnm yfd<br />
trp clt fmt nem mqt pmt vmy hmf ste gdh frv lvc rew rkl esh gek aen qgh pql yra ngf kgs<br />
qmw pfl stw rnv fkc yvq acd asm dvq gqc rsf nth vna lkt fmr kcy kyg akq gdk rqp nra fsv<br />
lsg thm gda ldm dls pdp fti nan vyk wih ndn yfa hqt nqt lhg tvw atf mig fyv rhr mrh eek<br />
cfr swv let fpc fce kei dis prd qdl act
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
49. yfm nrt dyv nhe iak asr gkm qne vqn nkd haf cmm fam myw ghd igt nmr phc shy<br />
kvk vdd vnh hqv wme hfi pnk qse kgv hlg vqs mdi ldp lvk ckm atk kcw sgc ydc qry htt<br />
kia vgy gcg clh sgc kag fln qiw nfm fwg hra ttl nrw ydg fqg vtl pgp gya csw rym prm fta<br />
svf feq kra cne wyw iim fiv lgk pmq qid pgc wqy kra det vea mwt enr sqw emg tpr sep<br />
pem lrq pqa yft qei fry lqh qve qac cvg iiy ews wwp pfm hhi lqi rrc wfc mla icn itg fkw<br />
wkc hyt vnv rmp sgn cvr mpc sny aly rpy fqq pir isv ehv gik grw skr vlw fgg spc yih afr<br />
nti fpc sev tkp fas aim veg rng kvr avd ywv iqf tya syq mwh qkg pwi khv sef ath grp nvq<br />
lrn fqs wlw fmf hnr ycw lhy yvt ytc aia yiy gnm cna tfp kct lve ivd tks tmp ica tyf ckn<br />
syp qva iam ygk gni rev des iqn pft pin ilt ivh hpr tnp qqt psd ynk kia efy cpm hsy idl nec<br />
mai eri evh wvg nmi keh hvq ggh aak ttl rlr fce yts tep lwr mad qpw hhn efm asw pmt<br />
fvv cqg acw nde gip wlt are wcr ggi qnc ytn gcr stn twa gyl kan smq rhk qha lyt gkd asv<br />
mdg tcw rds ffk mwh gkg ack fqn cgm arv kgk egl rgn dvt ffh rcl ydg wsr ksv nlw lra sgs<br />
qlt gss nyw hlm sem lfd edc glm egy nmn mit ecc eme dte mds lwg php tad anh eiw sgv<br />
yyv cyf gms inw glq vaw mah car isv ary yml ndv vmr hnv cah amy tir cws lnd rel vfa rfc<br />
mei ndl gee ppa rqf cka ttw wwt lrv ncn lvh qgm pqa vyl hka qyk fcv tki vyk rfs mfn vcs<br />
rcn fas hnr hti tsk nmc gkg fps inq nhv ari gkq ett hha cys lnh sny dyr yng fhh vqq ttc<br />
mac anv gge rsp tps asd iea nhn gkv gqq fai sye psh gly hkc yvd khs dey ivt lvt dcc ftr<br />
lmg cgv ffs gfc lar yvr ifw ssm hqc sar gqm yei wky gpm pfs ldc gnc hph wqd qsv wen<br />
ily inh hrk enr rgw mir nen rit rdp qwv fik<br />
50. ene cdh gda aes ekm dtk heq vki eht cff vhg afp qsw tpe eee gvf ieg mdr dhv tmr sdf<br />
hag wap pfa kdv yea phs nqe edc eey lml egq vrc kan elq ram avk frv vdf gpq wck aty isy<br />
yaf nlv pyd lae pmp rwr mwg vpe ttg wln gcl stf vlm nvw asc rfe kkm pqy lll dnh fgc tcp<br />
idy ydd pfq civ ikr qdm nma mwi fwi ltq vki wrf cnv fhw gtt edg ffp twn eyc hms evm<br />
spr pst tle wng mee cfe rrt yyq kid csp ryd fci nlg rlc pmy tst dlw trk lav qrw ihl aqv yth<br />
atg gac qve cny kky tfe rhf gvw lwc nrv lmr gmq vap kgd qkr ynh asn pec sqy che gkt<br />
vav nyl ecq avf aqe icl wtr aav ryg adq vts hre meg paq cdn eqs see htw wsl ggd pld ysa<br />
nrf rhp wnr gmg sqt pls wdd ict smq wyl grs gcl crt wvn vdr ncf wrt gqm yah cal ite fwn<br />
rcq ehk fwl fng nsh lyi ptt mew awq swq inh qiy fsk lar wcf spr ytc ckg kvs nwp eqf vya<br />
ftq mpv ges erd lqq gfy cvy isn ypc ahr qem yad tmt ecp vpt ffl mce ghw ltv mms qss pnv<br />
yfw svq ndq sac gmq pyk fie wdc pmr ept mgs yer cip gfh yvc nli lrn fqf ntg knd wkr pyy<br />
sfp asl tst fqs msf qrg gen kcn mgd wqp pae mmc qrr tqn flt gqn wii cme ppn fih fsr crq<br />
mha ggh klg eim tnq mac ilq hpw rsp qhk kdq mwp lee hhd ntm hpg elf ikv wrd cml lmi<br />
epv ism lvv vta gms nvn pte qet pci dvh fqn als eqf kdn cig kkn dfg gld tfd lri lde gkf ryy<br />
qne qpm pch nmg syq snw rvp psn fva rcn klp cgg cnh lvt wpm glw qtt nni nye mrq mdp<br />
ywr crd rwn esq cvl qkw dvs qyl hhk nak dnc ckk ygq asg ivt hrs kwi sir dgn edr lic laa<br />
ffh pmt rlt itr kdy fgc iqh kmv fdi ddm nke wrt lly apt vep ltt ris mhf iht cpn wes dtq wpd<br />
cri wni rqc pcr mhc rca qck ist frn fan awe fyr ndq vai gpq vgr tgm vvw qpg sdp aev pdh<br />
mdh fww dly ecq vlf tqp
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
Appendix II: Single-letter Abbreviations for the twenty amino acids<br />
The amino acids used in proteins can be refered to by a single letter. These<br />
abbreviations are given below. So, in a sense, the amino acid sequence of a protein can<br />
be spelled using a 20 letter alphabet (acdefghiklmnpqrstvwy). (That it, all the letters in<br />
the English alphabet except b, j, o, u, x, and z)<br />
Nonpolar Amino Acids<br />
A = Alanine<br />
G = Glycine<br />
V = Valine<br />
L = Leucine<br />
I = Isoleucine<br />
M = Methionine<br />
F = Phenylalanine<br />
W = Tryptophan<br />
P = Proline<br />
Polar Amino Acids<br />
S = Serine<br />
T = Threonine<br />
C = Cysteine<br />
Y = Tyrosine<br />
N = Asparagine<br />
Q = Glutamine<br />
Negatively Charged Amino Acids<br />
D = Aspartic Acid<br />
E = Glutamic Acid<br />
Positively Charged Amino Acids<br />
K = Lysine<br />
R = Arginine<br />
H = Histidine
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
<strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Activity I: Simulating The Generation of a Diverse and Self-Tolerant Tcell<br />
Repertoire<br />
<strong>By</strong> Dan O’Connell<br />
St. Andrew’s School<br />
350 Noxontown Rd.<br />
Middletown, DE 19709<br />
Introduction:<br />
This activity is intended as a homework assignment. To complete this activity properly,<br />
students must have internet access. If internet access is not feasible, Appendix I can be<br />
used instead. Appendix I contains fifty sets of 3-letter sequences, with four-hundred<br />
three-letter sequences in each set. Before you begin this activity you will need to have<br />
carefully read the scientific background section of this unit.<br />
In this activity we will simulate the production of immunological diversity by generating<br />
random letter sequences. The central idea in this activity is that the amino acid<br />
composition of various antigen-binding sites can be represented by sequences of letters.<br />
These letter-sequences are generated using a random-letter-generator. The randomness<br />
of letter selection is loosely analogous to the diversification that takes place during the<br />
gene-segment splicing that occurs during genetic recombination in early B-cell and T-cell<br />
development (See Scientific Background). It is important to keep in mind that the<br />
number of amino acids that actually make-up an antigen-binding site can vary. In this<br />
activity 3-letter sequences are used to represent the amino acids that make up different<br />
antigen-binding sites. However, the number of amino acids needed to make a realistic<br />
antigen-binding site is more than three. Using three-letter sequences to represent<br />
antigen- binding sites is a simplification. Unfortunately, this simplification is a practical<br />
necessity. If longer amino acid sequences were used, the diversity of the antigenbinding-site<br />
pools would become unmanageably large. Trying to determine whether a<br />
particular antigen-binding site is present in the pool would be like looking for a needle in<br />
a haystack. In order to make this simulation more practical, the size of the haystack had<br />
to be drastically reduced. This was achieved by limiting the size of the antigen-binding<br />
site sequence to only three amino acids.<br />
There are twenty letters in the random letter alphabet because there are twenty amino<br />
acids typically found in proteins. With only three letters in each antigen-binding-site<br />
sequence, the number of possible sequences is 20 3 or 20x20x20, which equals 8,000. If<br />
thirty students are in a class, and each generates 400 sequences, then the total number<br />
of sequences generated would be 12,000. With this number of sequences, there is a<br />
reasonable chance that any of the 8,000 possible sequences will be represented. Of<br />
course, there is no guarantee that every one of the 8,000 possible sequences will be<br />
represented among the 12,000 generated by twenty students. This is because the<br />
sequences are generated randomly and could include some repeats. With a smaller<br />
class, the chance of having gaps in the sequence set increases.<br />
One other simplification that should be kept in mind is that the antigen-binding site<br />
sequences would not tend to bind to matching (i.e. identical) antigen sequences.<br />
Indeed, some antigens are not even peptides. Instead, there needs to be molecular<br />
complementarity between the two partners in a binding interaction. However, there is<br />
no simple rule for predicting complementarity. So, identical matching is being used as a<br />
proxy for the more biologically accurate event—molecular recognition between antigens<br />
and antigen-binding sites. Those TCRs with the right amino acid sequence to produce an<br />
antigen binding site with high affinity for a particular antigen are said to recognize that<br />
antigen.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
Step 1: Using Appendix II answer the following questions:<br />
What amino acid is represented by the single-letter abbreviations below:<br />
G P Y<br />
D R H<br />
Step 2.<br />
Visit the random letter generator provided at the web site<br />
http://www.creighton.edu/~davereed/Nifty/randSeq.html<br />
a. In the box labeled “Letters to choose from” set the alphabet to acdefghiklmnpqrstvwy.<br />
(That is, the English alphabet except b, j, o, u, x, and z).<br />
b. In the box labled “Length of each random letter sequence” enter the number 3.<br />
c. In the box labled “Number of random letter sequences to generate” enter the number 400.<br />
d. Generate the 400 3-letter sequences.<br />
e. Copy the results produced by the random sequence generator and paste them into a<br />
word-processing program.<br />
f. Print the 400 sequences. These will be used in class during Activity II.<br />
Step 3. Repeat Step 2, but this time, in the box labled “Number of random letter sequences to<br />
generate” enter the number 1. Write the result here .<br />
Step 4:<br />
Answer the questions below.<br />
Question 1: Why were the letters b, j, o, u x, y and z not included in the “letter to<br />
choose from” field in step 2a above?<br />
Question 2: If each student uses the random letter generator independently, will any<br />
two students be likely to come up with identical sets of the same four hundred threeletter<br />
words? If so, why? If not, why not?<br />
Question 3: If each student uses the random letter generator independently, will any<br />
two students be likely to come up with any of the same three-letter words? If so, why?<br />
If not, why not? (Read this carefully, it is not the same as the question above).<br />
Question 4: Write down the first four triplets in your set of 400 using the full name for<br />
the amino acids, not the single letter abbreviations. For example, if you obtained the<br />
triplet “aar” write “alanine-alanine-arginine.”
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
Question 5: Why is the use of a sequence of only three amino acids a simplification of<br />
the more complex biological reality? Explain.<br />
Question 6: Why does it make sense to use a random-letter generator in order to<br />
derive a diverse set of sequences? Surely, the immune system does not have a randomletter<br />
generator. What does happen in the immune system that is analogous to the<br />
random-letter generator?<br />
Question 7: You may recall that triplets of RNA nucleotides are used to specify the<br />
amino acids incorporated in proteins during translation. Are the three-letter sequences<br />
used here the same? Explain. What are the three-letter sequences here representing?<br />
Question 8: Scan your set of 400 sequences (generated in step 2) to see whether any<br />
of the four hundred matches the one sequence generated in step 3. Did you find a<br />
perfect match? Yes No (circle one).<br />
Question 9: Should you have expected to find a match? If so, why? If not, why not?<br />
Question 10: A person with a healthy immune system possesses many millions of<br />
different, mature T-cells. The most crucial difference between these different T-cells is<br />
that each possesses a different TCR and therefore recognizes different antigens. Over a<br />
person life, his or her immune system is likely to encounter only a few hundred, or<br />
perhaps, a few thousand different pathogens. Given these numbers, would you expect a<br />
person with a healthy immune system to have a T-cell that specifically recognizes each<br />
pathogen encountered in a lifetime? Explain.
AAI Curriculum Unit: <strong>Understanding</strong> Diversity <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
TEACHER MATERIAL<br />
<strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Activity I: Simulating The Generation of a Diverse and Self-Tolerant Tcell<br />
Repertoire<br />
<strong>By</strong> Dan O’Connell<br />
St. Andrew’s School<br />
350 Noxontown Rd.<br />
Middletown, DE 19709<br />
Introduction:<br />
This activity is intended as a homework assignment. To complete this activity properly,<br />
students must have internet access. If internet access is not feasible, Appendix I can be<br />
used instead. Appendix I contains fifty sets of 3-letter sequences, with four-hundred<br />
three-letter sequences in each set.<br />
In this activity we will simulate the production of immunological diversity. The central<br />
idea in this activity is that the amino acid composition of various antigen-binding sites<br />
can be represented by sequences of letters. These letter-sequences are generated using<br />
a random-letter-generator. The randomness of letter selection is loosely analogous to<br />
the diversification that takes place during the gene-segment splicing that occurs during<br />
genetic recombination in early B-cell and T-cell development (See Scientific Background).<br />
It is important to keep in mind that the number of amino acids that actually make-up an<br />
antigen-binding site can vary. In this activity 3-letter sequences are used to represent<br />
the amino acids that make up different antigen-binding sites. However, the number of<br />
amino acids needed to make a realistic antigen-binding site is more than three. Using<br />
three-letter sequences to represent antigen- binding sites is a simplification.<br />
Unfortunately, this simplification is a practical necessity. If longer amino acid sequences<br />
were used, the diversity of the antigen-binding-site pools would become unmanageably<br />
large. Trying to determine whether a particular antigen-binding site is present in the<br />
pool would be like looking for a needle in a haystack. In order to make this simulation<br />
more practical, the size of the haystack had to be drastically reduced. This was done by<br />
limiting the size of the antigen-binding site sequence to only three amino acids.<br />
There are twenty letters in the random letter alphabet because there are twenty amino<br />
acids typically found in proteins. With only three letters in each antigen-binding-site<br />
sequence, the number of possible sequences is 20 3 or 20 x 20 x 20, which equals 8,000.<br />
If thirty students are in a class, and each generates 400 sequences, then the total<br />
number of sequences generated would be 12,000. With this number of sequences, there<br />
is a reasonable chance that any of the 8,000 possible sequences will be represented. Of<br />
course, there is no guarantee that every one of the 8,000 possible sequences will be<br />
represented among the 12,000 generated by twenty students. This is because the<br />
sequences are generated randomly and could include some repeats. With a smaller<br />
class, the chance of having gaps in the sequence set increases.<br />
One other simplification that should be kept in mind is that the antigen-binding site<br />
sequences would not tend to bind to matching (i.e. identical) antigen sequences.<br />
Indeed, some antigens are not even peptides. Instead, there needs to be molecular<br />
complementarity between the two partners in a binding interaction. However, there is<br />
no simple rule for predicting complementarity. So, identical matching is being used as a<br />
proxy for the more biologically accurate event—molecular recognition between antigens<br />
and antigen-binding sites. Those TCRs with the right amino acid sequence to produce an<br />
antigen binding site with high affinity for a particular antigen are said to recognize that<br />
antigen.
AAI Curriculum Unit: <strong>Understanding</strong> Diversity <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
TEACHER MATERIAL<br />
Step 1: Using Appendix II answer the following questions:<br />
What amino acid is represented by the single-letter abbreviations below:<br />
G Glycine P Proline Y Tyrosine<br />
D Aspartic Acid R Arginine H Histidine<br />
Step 2.<br />
Visit the random letter generator provided at the web site<br />
http://www.creighton.edu/~davereed/Nifty/randSeq.html<br />
a. In the box labeled “Letters to choose from” set the alphabet to acdefghiklmnpqrstvwy.<br />
(That is, the English alphabet except b, j, o, u, x, and z).<br />
b. In the box labeled “Length of each random letter sequence” enter the number 3.<br />
c. In the box labeled “Number of random letter sequences to generate” enter the number 400.<br />
d. Generate the 400 3-letter sequences.<br />
e. Copy the results produced by the random sequence generator and paste them into a<br />
word-processing program.<br />
f. Print the 400 sequences. These will be used in class during Activity II.<br />
Step 3. Repeat Step .2, but this time, in the box labeled “Number of random letter sequences to<br />
generate” enter the number 1. Write the result here .<br />
Step 4:<br />
Answer the questions below.<br />
Question 1: Why were the letters b, j, o, u x, y and z not included in the “letter to<br />
choose from” field in step 2a above?<br />
Because there none of the standard twenty amino acids has a one-letter abbreviation<br />
using any of these letters.<br />
Question 2: If each student uses the random letter generator independently, will any<br />
two students be likely to come up with identical sets of the same four hundred threeletter<br />
words? If so, why? If not, why not?<br />
No each student is expected to have a unique set of sequences. Since there are 8000<br />
possible three-letter sequences, there are many sets of 400 that can be made by<br />
selecting from this pool. It would be extraordinarily unlikely that two would happen to<br />
produce the same set of 400. One way to assure yourself of this is to look at Appendix I.<br />
Notice the appendix includes fifty sets of sequences and each set is different from every<br />
other.<br />
Question 3: If each student uses the random letter generator independently, will any<br />
two students be likely to come up with any of the same three-letter words? If so, why?<br />
If not, why not? (Read this carefully, it is not the same as the question above).<br />
Yes, it is expected that the same three-letter word will come up more than once. This is<br />
becauseeach student has four hundred opportunities to find a match with a classmate<br />
and presumably, there are many classmates. So there are many opportunities for<br />
matches. One way to convince yourself this is the case is to look at Appendix I. You can<br />
see that “mdn” is the first sequence in the first set. The sequence “mdn” also occurs on<br />
the last line of the 36 th set. To further convince yourself, look at the next few sequences<br />
from the first set: yqf occurs twice in the fifty sets. “ntg” occurs three times and hyy<br />
occurs six times.
AAI Curriculum Unit: <strong>Understanding</strong> Diversity <strong>By</strong> <strong>Tracing</strong> T-cell <strong>Development</strong><br />
TEACHER MATERIAL<br />
Question 4: Write down the first four triplets in your set of 400 using the full name for<br />
the amino acids, not the single letter abbreviations. For example, if you obtained the<br />
triplet “aar” write “alanine-alanine-arginine.”<br />
methionine-aspartic acid-asparagine tyrosine-glutamine-phenylalanine<br />
asparigine-threonine-glycine histidine-tyrosine-tyrosine<br />
Question 5: Why is the use of a sequence of only three amino acids a simplification of<br />
the more complex biological reality? Explain.<br />
Because the three-letter sequences is much shorter than the biological reality. In reality,<br />
a TCR is a protein composed of hundreds of amino acids and its antigen binding site<br />
might include dozens. We use three here to keep from having an overwhelmingly<br />
diverse set of sequences.<br />
Question 6: Why does it make sense to use a random-letter generator in order to<br />
derive a diverse set of sequences? Surely, the immune system does not have a randomletter<br />
generator. What does happen in the immune system that is analogous to the<br />
random-letter generator?<br />
During lymphocyte development various gene segments are joined together to construct<br />
TCR and antibody genes. The variety of possible genes that can be formed by this<br />
recombinatorial process is large. Also, the proteins produced by these genes have<br />
unpredictable combinations of amino acids. Likewise, the random-letter generator puts<br />
together letters randomly. This makes random-letter generation an imperfect, but useful<br />
analog for genetic recombination.<br />
Question 7: You may recall that triplets of RNA nucleotides (called codons) are used to<br />
specify the amino acids incorporated in proteins during translation. Are the three-letter<br />
sequences used here the same? Explain. What are the three-letter sequences here<br />
representing?<br />
Absolutely not. The three-letter sequences here represent tri-peptides. The three letter<br />
codons of mRNAs specify the amino acid sequences of proteins, but it would take a<br />
nucleic acid sequence of nine nucleotides to specify the three amino acid sequence<br />
represented by the tri-peptide three-letter sequences used here.<br />
Question 8: Scan your set of 400 sequences (generated in step 2) to see whether any<br />
of the four hundred matches the one sequence generated in step 3. Did you find a<br />
perfect match? Yes No (circle one). Either answer is possible.<br />
Question 9: Should you have expected to find a match? If so, why? If not, why not?<br />
No. There are 8000 possible tri-peptides. In a set of 400 it is unlikely (although by no<br />
means impossible) that any one of the 8000 would be found.<br />
Question 10: A person with a healthy immune system possesses millions of different Tcells.<br />
The crucial difference between these different T-cells is that each possesses a<br />
different TCR and so recognizes different antigens. Over a person life, their immune<br />
system is likely to encounter only hundreds, or perhaps, a few thousand different<br />
pathogens. Given this, would a person with a healthy immune system probably have a<br />
T-cell that specifically recognizes each pathogen encountered in a lifetime? Explain.<br />
Remember, the immune system generates an enormously diverse populaition of T-cells.<br />
Of course, most of the T-cells that are made are lost during positively selected or<br />
negative selection. Still, the number different mature T-cells is estimated to be of the<br />
order of tens of millions or more. So, it is likely that there will be a TCR capable of<br />
recognizing antigen from almost any of the thousands of possible pathogen. Although it<br />
is possible an antigen will exist for which no TCR is a good match, the sheer diversity of<br />
the TCR repertoire makes this unlikely.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
<strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Activity II: The <strong>Thymocyte</strong> Game of Life<br />
Complete Rules<br />
<strong>By</strong> Dan O’Connell<br />
St. Andrew’s School<br />
350 Noxontown Rd.<br />
Middletown, DE 19709<br />
The Object: The object of the game is to be the first player to recognize an invading<br />
pathogen and undergo T-cell activation. <strong>By</strong> playing this game you will be challenge to<br />
demonstrate understanding of the generation of immune diversity, negative selection,<br />
positive selection and T-cell stimulation by antigen. Before you begin this activity you<br />
will need to have carefully read the scientific background section of this unit.<br />
Materials Needed:<br />
Game Pieces<br />
Dice (one pair of six-sided dice for each group of students)<br />
Game Board<br />
Scientific Background Document<br />
Random-letter generator or Appendix I<br />
Random-letter generator or Scrabble® tiles<br />
Note: It will probably be best if there are no more than six to eight game pieces on any one<br />
board, so students may be assigned to teams, and/or more than one board may be used.<br />
How to Play: Play begins by players cutting out game pieces and labeling them with<br />
their names. Each game piece contains 400 squares in a grid. The game piece<br />
represents your repertoire of immature thymocytes. To win the game you must<br />
successfully overcome five key challenges in the life of a thymocyte. Each of these<br />
challenges is set apart on a different part of the board. To move from one part of the<br />
board to another, you roll a pair dice and move the corresponding number of spaces. If<br />
you roll more than the required number, you may stop your movement at the desired<br />
location. The board permits movement freely in several directions. You must start at<br />
the space labled “start” (in the bone marrow) and complete the challenges on the<br />
spaces marked with a bold double-rectangle. Each player is responsible for choosing the<br />
correct path in order to complete each of the five challenges of T-cell maturation in the<br />
proper sequence.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Game Pieces:<br />
Each grid contains 400 quadrants. Each of these 400 quadrantss can be thought of as individual<br />
thymocytes in your immune repertoire. You should cut out one grid, write your name on it and<br />
use it as your game piece.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
The Five Challenges: The requirement for each challenge is slightly different. Each<br />
challenge has its own set of rules. In order to complete a challenge you must land your<br />
game piece on the specially marked spaces. These special spaces are marked “Start”,<br />
“Thymic Cortex”, “Cortico-medullary Junction”, “Travel to the Periphery”, and “Lymph<br />
Node”.<br />
The Thymic Cortex 1 -- The Generation of Immune Diversity:<br />
Each player begins the game in the bone marrow because this is where the<br />
precursors of T-cells are first formed. In the bone marrow, hematopoietic stem<br />
cells divide to give rise to T-cell precursors, called thymocytes. Later, in the<br />
thymus, thymocytes undergo somatic genetic recombination to produce a highly<br />
diverse population of cells. The thing that makes this population of cells so<br />
diverse is that the vagaries of recombination cause different cells to have<br />
different TCR genes. The three-letter sequences, generated in Activity I,<br />
represent the different antigen-binding sites of the TCRs. These TCRs are found<br />
on the surface of the thymocytes produce in the bone marrow. In order to<br />
proceed to the second challenge in the thymic cortex, you must:<br />
1. Complete Activity I, and thus, have a set of 400 hundred<br />
three-letter sequences, and;<br />
2. Explain what your set of three letter sequences represent.<br />
3. Correctly describe roughly how many different types of<br />
thymocytes the human body can produce through genetic<br />
recombination.<br />
The Thymic Cortex 2 —Positive Selection:<br />
Before thymocytes can be of use they must be able to interact with other cells in<br />
the body. One interaction of particular importance is the binding of T-cell<br />
receptors to “major histocompatibility complex” (MHC) proteins. Only those<br />
thymocytes that are capable of performing this interaction are able to mature<br />
further. The process by which thymocytes are signaled to mature by engaging<br />
the MHC of thymic cortex cells is called positive selection. All the cells that are<br />
not positively selected for their ability to engage MHC, quickly die. The death of<br />
these cells is sometimes called “death by neglect” and is accomplished through<br />
apoptosis. Positive selection and death by neglect ensure that all mature T-cells<br />
have TCRs that can interact with the MHC. Typically, only about 10% of the<br />
thymocytes generated in the bone marrow succeed in being positively selected.<br />
The remaining cells succumb to death by neglect. To simulate this, each player<br />
must select one amino acid from the list of 20 (acdefghiklmnpqrstvwy). Selecting<br />
this amino acid can be easily accomplished by using the random-letter generator,<br />
setting the length of the sequence to one. (See Activity I). Having selected one<br />
amino acid you must now cross out all three-letters sequences (in your set of<br />
400 sequences) that do not include the selected amino acid. For example, if the<br />
selected amino acid were alanine the three-letter sequence “gci” or “kde” would<br />
have to be stricken from the repertoire but the sequence “nna” would not. This<br />
process should result in about 90% of the three-letter sequences being deleted<br />
from the repertoire. The three-letter sequences that did happen to possess the<br />
selected amino acid survive. They have succeeded in passing the challenge of<br />
positive selection and can continue to mature. The cells remaining in the<br />
repertoire at this stage are said to be MHC-restricted.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
In order to leave the thymic cortex you must:<br />
1. Reduce your thymocyte repertoire through positive selection.<br />
2. Explain the purpose of positive selection.<br />
The Cortico-medullary Junction-- Negative Selection:<br />
The MHC-restricted thymocyte repertoire must be screened yet again. This time<br />
the thymocytes that need to be eliminated are those that happen to possess<br />
TCRs that interact too strongly with self. The way we simulate this is by<br />
scanning the remaining three-letter sequences for any that spell actual words in<br />
the English language. For example, if your MHC-restricted repertoire possesses<br />
three-letter sequence, such as, dad, age, egg, or pee. These would have to be<br />
crossed out. These sequences represent those TCRs that would recognize self.<br />
Failure to eliminate all such thymocytes could result in auto-immune disease.<br />
In order to leave the Cortico-medullary Junction you must:<br />
1. Reduce your thymocyte repertoire through negative selection.<br />
2. Explain the purpose of negative selection<br />
Travel to the Periphery:<br />
After completing positive and negative selection thymocytes are now called Tcells.<br />
These cells are mature but are so-called “naïve.” These T-cells migrate<br />
through the medulla of the thymus and enter blood vessels. T-cells move out to<br />
all parts of the body where they enter the bodies tissues and recirculate to the<br />
blood via the lymphatic system. There is no special challenge at this stage of the<br />
game, just moving from the thymus to the blood to the lymph.<br />
In order to exit the thymus and travel to the periphery you must:<br />
1. Simply move your game piece.<br />
2. Explain what would happen if an immature thymocyte<br />
traveled directly to the periphery without first undergoing<br />
maturation in the thymus.<br />
The Lymph Node-- Antigen Recognition and T-cell Activation:<br />
It is within lymph nodes (and other secondary lymphoid tissues) that T-cells<br />
typically encounter pathogens. The challenge at this stage is, in a sense, a<br />
waiting game. It is quite possible that a particular T-cell will live its entire life<br />
without ever encountering a pathogen whose antigen has just the right<br />
properties to be recognized. Indeed, almost all T-cells will live dormant lives,<br />
never being called to actually do anything. However, we are constantly<br />
encountering pathogens so at any given time there will be at least some small<br />
fraction of the T-cell repertoire that is actively toiling to protect the body. When<br />
a T-cell’s TCR binds tightly to an MHC presenting the right antigen, this binding<br />
helps trigger activation of this T-cell. To simulate this process, set up the<br />
random-letter generator as follows:<br />
Visit the random letter generator provided at the web site<br />
http://www.creighton.edu/~davereed/Nifty/randSeq.html<br />
a. In the box labeled “Letters to choose from” set the alphabet to<br />
acdefghiklmnpqrstvwy. (That is, the English alphabet except b, j, o, u, x, and z).<br />
b. In the box labeled “Length of each random letter sequence” enter 2.<br />
c. In the box labeled “Number of random letter sequences to generate” enter 1.<br />
d. Generate the three-letter sequence.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
e. Compare the three-letter sequence generated in step d above with all the<br />
three-letter sequences that have survived positive and negative selection. 1<br />
The first player to successfully match a three-letter sequence in his or her mature T-cell<br />
repertoire with the two-letter sequence generated in step d, above, is the winner of the<br />
game. If there are no matches, repeat the steps above until a match is found. In order<br />
to have a match between the three-letter TCR sequence and the two-letter antigen<br />
sequence their can be no gaps in the matching sequence. So, for example, aga would<br />
be a match for the two letter sequences “ag” and “ga” but not for “aa.”<br />
In order to win you must achieve T-cell activation. To do this you must<br />
1. Match one of the three-letter sequences in your mature T-cell<br />
repertoire with one of the two-letter sequences representing an<br />
antigen.<br />
2. Describe the additional developmental events that are triggered<br />
by T-cell activation.<br />
3. Briefly explain how a differentiated T-cell, such as a cytotoxic T-cell,<br />
helps rid the body of pathogens.<br />
1 If using the random-letter generator is inconvenient, it is simple to generate a small<br />
number of random-letter sequences by pulling letters from a bag. Scrabble tiles work<br />
well.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Activity II: The <strong>Thymocyte</strong> Game of Life<br />
Concise Rules<br />
The Object: The object of the game is to be the first player to recognize an invading<br />
pathogen and undergo T-cell activation.<br />
How to Play: To win the game you must successfully overcome five key challenges in<br />
the life of a thymocyte. You roll a pair dice to move your game piece. You must<br />
complete the challenges of T-cell maturation in the proper sequence. You must start at<br />
the space labeled “start” and complete the challenges on the spaces marked with a bold<br />
double-rectangle.<br />
The Five Challenges: After leaving the bone marrow, you must move<br />
through the board completing the following challenges:<br />
The Thymic Cortex 1—Generating A Diverse <strong>Thymocyte</strong> Repertoire<br />
1. Complete Activity I, and thus, have a set of hundreds of threeletter<br />
sequences;<br />
2. Explain what your set of three-letter sequences represent; and<br />
3. Correctly describe roughly how many different types of<br />
thymocytes the body can produce through genetic recombination.<br />
The Thymic Cortex 2-- Positive Selection:<br />
In order to leave the thymic cortex you must:<br />
1. Reduce your thymocyte repertoire through positive selection.<br />
2. Explain the purpose of positive selection.<br />
The Cortico-medullary Junction-- Negative Selection:<br />
In order to leave the Cortico-medullary Junction you must:<br />
1. Reduce your thymocyte repertoire through negative selection.<br />
2. Explain the purpose of negative selection<br />
Travel to the Periphery--<br />
In order to exit the thymus and travel to the periphery you must:<br />
1. Simply move your game piece.<br />
2. Explain what would happen if an immature thymocyte<br />
traveled directly to the periphery without first undergoing<br />
maturation in the thymus.<br />
The Lymph Node-- Antigen Recognition and T-cell Activation: In order to<br />
win you must achieve T-cell activation. To do this you must<br />
1. Match one of the three-letter sequences in your mature T-cell<br />
repertoire with one of the two-letter sequences representing an<br />
antigen.<br />
2. Describe the additional developmental events that are triggered<br />
by T-cell activation.<br />
3. Briefly explain how a differentiated T-cell, such as a cytotoxic T-cell,<br />
can help rid the body of pathogens.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Game Pieces:<br />
Each grid contains 400 quadrants. Each of these 400 quadrantss can be thought of as individual<br />
thymocytes in your immune repertoire. You should cut out one grid, write your name on it and<br />
use it as your game piece.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Activity III: Why do Mature T-cells Respond To stimulation Differently<br />
From Immature Cells?<br />
<strong>By</strong> Dan O’Connell<br />
St. Andrew’s School<br />
350 Noxontown Rd.<br />
Middletown, DE 19709<br />
In studying the scientific background section, you read that TCR-stimulation of immature<br />
thymocytes causes those thymocytes to undergo apoptosis, yet, the very same<br />
stimulation, will, cause a mature T-cell to proliferate and differentiate. What could be<br />
more unexpected—in one case stimulation caused a cell to kill itself and in another case,<br />
causes the cell to create many copies of itself. Of course, this is exactly what is needed<br />
for the immune system to function well. If a mature T-cell experiences TCR-stimulation<br />
it is likely the T-cell has recognized a pathogen-derived antigen. It makes sense that this<br />
very cell would make many copies of itself. That would give the body a whole arsenal of<br />
cells that recognize a known invader. In contrast, an immature thymocyte is likely to be<br />
stimulated by host-derived antigen. So, in this circumstance, it makes sense that the cell<br />
kill itself. A self-reactive T-cell would have only caused auto-immune trouble if allowed<br />
to survived to prowl the periphery.<br />
Just because these cells are responding in ways that make sense, functionally, the<br />
question remains. How do these cell know how to do the right thing? Dr. Punt, and<br />
others, have wondered how T-cell maturation could cause it to respond so differently to<br />
stimulation. What is different about the mature T-cell? How has the apoptosis signal<br />
been cancelled? How does the signal to differentiate and proliferate get communicated?<br />
Something must have changed within the immature cell to account for such radical<br />
change in the way it responds to TCR binding. The full details of this change are not yet<br />
known. Instead, this question is being actively investigated. in Dr. Punt’s laboratory, and<br />
others. One reasonable hypothesis is that the molecules that convey signals from the<br />
cell surface differ in some important way in mature verses immature thymocytes.<br />
Several such signal-transduction molecules are being investigated for their role in<br />
triggering apoptosis and/or proliferation. One molecule of special interest is Nur77.<br />
Nur77 is a steroid receptor that acts as a transcription factor—a protein that triggers the<br />
transcription of genes. When Nur77 is over-expressed in an immature thymocyte, the<br />
cell undergoes apoptosis. It has also been shown that expression of Nur77 in transgenic<br />
mice results in a sharp increase in the quantity of several mRNAs. Since Nur77 is a<br />
transcription factor this is exactly what one would expect. It may be that the proteins<br />
encoded by these mRNAs are important in causing apoptosis.<br />
One way of examining the importance of transcription to apoptosis is to purify the<br />
mRNAs from mature and immature cells after each has had its TCRs stimulated by<br />
binding to antigen-like molecules. If some mRNAs are highly expressed in immature cells<br />
but not in mature cells, these mRNAs may be involved in bringing about apoptosis.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Figure 1: Investigating Gene Expression in <strong>Thymocyte</strong>s at Different <strong>Development</strong>al Stages<br />
Together with Dr. Punt, I investigated differences in the quantities of various mRNAs in<br />
TCR-stimulated mature T-cells compared with TCR-stimulated immature cells. Activity III<br />
presents some of the data obtained in this investigation. It is intriguing to consider that<br />
changes in the abundance of certain mRNAs might lead to the radically different<br />
responses of T-cells to stimulation at different points in their maturation.<br />
One technique that is used to examine this is called “Quantititative RT-PCR.” See Figure<br />
1. The first step in this process is to isolate immature and mature thymocytes. Since<br />
mature T-cells exit the thymus and congregate in lymph nodes, it is possible to isolate<br />
mature T-cells from lymph nodes. Likewise, isolating immature thymocytes is fairly<br />
straightforward, since these cells are localized to the thymus. Once these two types of<br />
cells have been isolated they are exposed to molecules that simulate TCR binding<br />
partners. This is called “stimulation.” Shortly after the two types of cells have been<br />
stimulated they are broken open and their mRNA is purified. The mRNA is fragile and so<br />
is reverse transcribed to produce a hardy DNA copy, called complementary DNA (or<br />
“cDNA”). This DNA is then amplified using the polymerase chain reaction. If, in fact,<br />
stimulation of immature thymocytes caused in increase in the transcription of certain<br />
genes, there should be more of the mRNA for these genes in the immature cell RNA<br />
preparations than the mature T-cell preparations. Consequently, there should be more<br />
DNA for these genes in the cDNA preparations. If so, amplification of these cDNA<br />
preparations should reveal DNA being produced by PCR in greater quantity in the<br />
immature cells than in the mature cells.<br />
One way of measuring the quantity of DNA produced in a PCR experiment is to separate<br />
the DNA on a gel. This technique, called gel electrophoresis, causes DNA molecules of<br />
different sizes to migrate to different positions on the gel. The smallest molecules find it<br />
relatively each to squeeze through the gel matrix, and so, migrate the farthest. The<br />
larger molecules migrate more slowly.
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Below is a image of the electrophoretically separated DNA molecules produced by the<br />
quantitative RT-PCR of three genes: actin, NDG1, and TCF4. Answer the question at the<br />
bottom of the figure legend—What do these data suggest about the relative abundance<br />
of the three mRNAs (actin, TCF4 and NDG1) in mature verses immature TCR-stimulated<br />
cells?
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
<strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Introduction, Acknowledgements and Scientific Background<br />
<strong>By</strong> Dan O’Connell<br />
St. Andrew’s School<br />
350 Noxontown Rd.<br />
Middletown, DE 19709<br />
I. Introduction<br />
This curriculum unit is intended as a resource for educators teaching immunological concepts to high<br />
school students. The unit is likely to be most appropriate for use in an advanced course, such as<br />
advanced placement biology, or for students with a special interest in the immune system. This unit<br />
consists of three related activities. Activity I uses a random-letter generator to simulate the<br />
generation of immunological diversity. Activity I is intended to be completed as a homework<br />
assignment in preparation for Activity II. At the conclusion of Activity I each student has created a<br />
set of letter sequences that represent a population of hundreds of genetically distinct thymocytes.<br />
Activity II is a board-game in which each player steers this population of thymocytes through their<br />
essential developmental stages. The first player to complete these stages and recognize antigen<br />
wins. Activity III presents students with a set of data on the abundance of different mRNAs in<br />
mature and immature thymocytes. Activity III challenges students to analyze primary data in order<br />
to understand the molecular basis for differences in thymocyte response upon stimulation by antigen.<br />
Note: Each student will need a copy of the scientific background section of this document<br />
in order to prepare for each of the three activities.<br />
A. Learning Objectives:<br />
The goal of this unit is to help students understand the following:<br />
1. The immune system plays a fundamental role in everyday life.<br />
2. Infectious disease has tremendous global impact on human health.<br />
3. Advances in our understanding of the immune system may have enormous practical<br />
importance, specifically, on public health and the treatment of disease, including:<br />
a. autoimmune disease<br />
b. infectious disease<br />
c. cancer<br />
d. tissue/organ transplant tolerance.<br />
4. Although scientists have learned a great deal about immune function, the process of scientific<br />
inquiry is ongoing. Even as we answer some of the fundamental questions about immune<br />
systems, additional questions continually arise.<br />
5. The following fundamental insights into immune system function<br />
a. adaptive immunity is made possible when somatic genetic recombination gives rise to<br />
diverse repertoires of B and T lymphocytes.<br />
b. specificity in the immune system is made possible by the complementarity of antigens<br />
for antigen-binding sites<br />
c. T-cells recognize antigens that are cradled in a presenting MHC molecule.<br />
d. the T-cell repertoire is a subset of the thymocyte repertoire. Positive selection<br />
ensures that mature T-cells can recognize the MHC.<br />
e. self-tolerance is achieved through apoptotic purging of self-reactive lymphocytes.<br />
6. Each mature, differentiated cell in a multicellular animal is the product of a particular<br />
developmental pathway.<br />
7. <strong>Development</strong> is regulated both by intracellular events (such as changes in gene expression)<br />
and by external cues (such as stimulation of cell-surface receptors by ligands).<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
B. Important Prior <strong>Understanding</strong>s<br />
Students should already be familiar with the following concepts:<br />
1. Genes encode the amino acid sequences of proteins.<br />
2. Proteins are crucial participants in nearly all biological phenomena. They are, by and large,<br />
the actors that perform the molecular events that make life possible.<br />
3. A protein is an amino acid polymer. The sequence of amino acids in the polymer determines<br />
the shape and other properties of the protein.<br />
4. The human genome contains about 25,000 protein-coding genes but not all genes are in use<br />
in all cells at all times. Instead, genes must be expressed. Gene expression is a regulated<br />
process.<br />
5. Bacteria, viruses, and other pathogens cause disease in humans and other organisms.<br />
6. Mammals have several non-specific defenses that complement the specific defenses of the<br />
immune system.<br />
7. Eukaryotic cells usually possess receptors on their surfaces. These receptors help relay<br />
information about the cell’s surroundings to the cell interior.<br />
II. Acknowledgements<br />
This unit was made possible by the generous support of the American Association of Immunologists<br />
(AAI). During the summer of 2004, the author was the recipient of an AAI John H. Wallace<br />
Fellowship. This fellowship enabled him to spend six weeks performing hands-on research in<br />
immunology in Dr. Jennifer Punt’s laboratory at Haverford College in Haverford, Pennsylvania. Dr.<br />
Punt was an inspiring teacher and a generous mentor.<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
<strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Scientific Background<br />
<strong>By</strong> Dan O’Connell<br />
St. Andrew’s School<br />
350 Noxontown Rd.<br />
Middletown, DE 19709<br />
A. An Overview of Immune Function:<br />
Even in a clean home, viruses, bacteria, fungi and other disease-causing organisms<br />
(called “pathogens”) pose a constant threat of infection. Sadly, pathogens typically kill<br />
about 15 million people each year. This is more than one quarter of all deaths<br />
worldwide. Indeed, more than twice as many people die each year from infectious<br />
disease as from all forms of cancer combined. Recent estimates place infectious disease<br />
at the very top of the list of causes of death worldwide. Still, mortality from infectious<br />
disease would be very much greater if people did not possess built-in systems for<br />
defending themselves from specific pathogens. For most people, pathogens are<br />
eliminated not by taking medicine, but instead, by the functioning of their body’s own<br />
defenses, such as their immune system.<br />
Day after day each of our immune systems engage in silent, invisible battles against an<br />
unending assault by invading organisms. In addition, the immune system protects the<br />
body from cancer by helping destroy precancerous or cancerous cells in the body. Each<br />
day that you experience health is a day that your immune system has prevailed in its<br />
battles. After each successful battle, the war continues each day of our lives. If you<br />
have lived a life free of disease, your immune system is surely part of the reason.<br />
In contrast, if you suffer from a weakened immune system, everyday battles against<br />
infection or cancer are more likely to be lost. One clear illustration of this fact is the<br />
great number of people suffering from acquired immune deficiency syndrome<br />
(“AIDS”) who succumb to otherwise controllable infections (such as pneumonia, or<br />
tuberculosis) or cancers (such as Kaposi sarcoma). Typically, human<br />
immunodeficiency virus (“HIV”) does not cause much direct bodily harm. Instead, by<br />
disabling immune cells, HIV infection makes it much easier for opportunistic<br />
infections to thrive.<br />
Although it is important to have a robust immune system, an over-aggressive system can<br />
also lead to serious illness. Our immune systems must be able to properly distinguish<br />
between our own healthy cells, and harmful invaders. The failure to properly draw this<br />
distinction can result in immune cells attacking our own tissues. This sort of self-directed<br />
attack, analogous to “friendly fire” on the battlefield, is the cause of autoimmune<br />
diseases. There are dozens of autoimmune diseases, including Type I diabetes, lupus,<br />
arthritis, multiple sclerosis and psoriasis.<br />
In addition to having a system that is robust in the face of invaders, but does not harm<br />
our own cells, it would be advantageous to many if their immune system tolerated the<br />
presence of a transplant. Currently, patients undergoing transplants risk transplant<br />
rejection; that is, they might lose the benefit of the transplants because their immune<br />
system attacks it. A common approach to this problem is to administer medication that<br />
suppresses the transplant-recipient’s immune system. Unfortunately, while this reduces<br />
the risk of transplant rejection, it simultaneously increases the risks associated with a<br />
weakened immune system.<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
In summary, the immune system helps protect our bodies from infectious disease and<br />
cancer but it also causes autoimmune disease and transplant rejection.<br />
Immunologists, the scientists who study the immune system, hope that by gaining a<br />
better understanding of the immune system, improvements can be made in our<br />
prevention and treatment of disease.<br />
<strong>By</strong> understanding the way our immune systems function, we will be better prepared to<br />
address infectious disease, autoimmunity, cancer and transplant rejection.<br />
Unfortunately, the complexity of the immune system makes it difficult to understand.<br />
The approach taken in this curriculum unit is to follow the development of thymocytes<br />
and T-lymphocytes. In the course of tracing the various possible developmental fates<br />
of thymocytes, this unit will explain how our immune system is capable of recognizing<br />
such a diverse set of invading organisms. Furthermore, it will teach how self-tolerance<br />
is achieved and how differential gene expression may cause mature T-cells to<br />
responding to stimulation very differently from immature thymocytes.<br />
B. The Generation of Immunological Diversity Involves Genetic Recombination:<br />
The immune system can be divided into two components: innate immunity and<br />
adaptive immunity. The innate system is good at reacting to certain invaders with a<br />
generalized response. For example, any of dozens of different bacterial species can<br />
trigger the same generic response (such as the complement cascade) because many<br />
bacterial species possess the same cell-wall components widely recognized by the same<br />
complement proteins.<br />
However, the adaptive system is capable of much greater specificity. Regardless of the<br />
invader, the adaptive immune system provides a specially tailored army of cells for<br />
responding to the particular invader. These specially tailored armies are specific because<br />
the cells that make them up possess proteins on their surface that can vary<br />
tremendously. Each different surface protein will bind to a different foreign substance.<br />
These foreign substances are called antigens. Most often, antigens are small pieces of<br />
a pathogen. In mammalian immune systems, antigens are usually fragments of a<br />
pathogen’s proteins. Some cells, such as macrophages are capable of engulfing<br />
pathogens, breaking the pathogens apart and then displaying the resulting fragments<br />
(i.e. antigens) on their surfaces. When a macrophage does this, it becomes an<br />
“antigen-presenting cell.” Most antigen presenting cells display a protein fragment of<br />
nine, ten, or eleven amino acids in length.<br />
Some of the most important immune system components are also proteins. Of particular<br />
importance are antibodies and T-cell receptors (“TCRs”). Antibodies are proteins that<br />
are secreted from certain immune cells (called plasma cells) and which bind antigens in<br />
the blood stream or other bodily fluid. Similarly, TCRs, which are structurally similar to<br />
antibodies, are found on the surface of T-cells. Antibodies and TCRs both consist of<br />
hundreds of amino acids. However, only a small subset of the amino acids of these<br />
proteins are directly involved in binding to antigens. This small sub-region of the<br />
antibody or TCR is called the antigen-binding site.<br />
Regardless of whether an invader is any of hundreds of different viruses, dozens of<br />
different bacteria or dozens of different eukaryotic parasites, the adaptive immune<br />
system is able to mount a response specific to that particular invader. If you pause to<br />
consider that pathogens are rapidly and continuously being altered by evolutionary<br />
processes, the specificity of the adaptive immune system can be seen to be even more<br />
remarkable.<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
How is it that our bodies can achieve specific responses to so many different and<br />
evolving invaders? Is it that we are each born with thousands of immunity genes<br />
capable of encoding thousands of different defenders? No! As a matter of fact, the<br />
number of genes associated with immunological diversity is far too small for this<br />
approach to work. Indeed, it has been found that the generations of copious<br />
immunological diversity can be accomplished using less than two thousand genes or<br />
gene segments. So, the question then is, how does the body generate a repertoire of<br />
millions of genetically different immune cell lineages without having millions of different<br />
immunity genes?<br />
The answer is “somatic cell genetic recombination.” Somatic cell genetic<br />
recombination is a bit like playing cards. Although there are only 52 different cards in a<br />
deck, there are 52 5 = 380,204,032 possible 5-card sequences! 1 Similarly, although there<br />
are only about two thousand immune system gene segments in a mammalian genome,<br />
there are millions of gene products that can be made by joining gene segments in<br />
different combinations. These different combinations ensure there will be a diverse<br />
repertoire of antibodies and TCRs each with a different antigen-binding site. Because<br />
recombination enables millions of different antigen binding sites to be produced, the<br />
number of antigens that can be specifically identified by the immune system is likewise in<br />
the millions. The details of recombination are complex and vary from one species to<br />
another. Among mammals, the process has been studied well in mice. In a mouse, any<br />
of about 300 different “V gene segments” can be combined with any of 4 different J gene<br />
segments to make 1200 possible VL genes. Each of these 1200 possible VL genes can<br />
produce any of 1200 different polypeptides. In addition, each of the VL polypeptides is<br />
partnered with any of 50,000 different VH polypeptides. These 50,000 possible<br />
polypeptides are themselves the result of the genetic recombining of a different set of V,<br />
J and D gene segments. (In the case of the production of VH any of about 12 D gene<br />
segments, 4 J gene segments and about 1000 V gene segments combine). When the<br />
possible VL polypeptides are paired with the possible VH polypeptides, we see there are<br />
about 50,000 x 1,200 = 60 million different antibodies or TCRs that can be produced<br />
using fewer than 2000 gene segments. In fact, the number of possible antibodies or<br />
TCRs is even more than 60 million due to the tendency of the gene-recombining<br />
mechanism to add or delete nucleotides at the junctions of gene segments. This<br />
process, called joining diversification, can add to the diversity of the immune<br />
repertoire, brining the number of different antibodies or TCRs above 60 million.<br />
The immune system consists of many different cell types, including macrophages—which<br />
ingest and kill pathogens and become antigen presenting cells; neutrophils—which<br />
release chemicals that kill pathogens and themselves; natural killer cells—which<br />
puncture and kill infected or cancerous cells; various B-lymphocytes (“B-cells”) and<br />
various T-lymphocytes (“T-cells”). Only B-cells and T-cells perform genetic<br />
recombination. In B-cells the recombinant gene encodes an antibody. The antibodies<br />
1 The number of hands of 5-cards is lower if the deck is not “bottomless” that is, if an ace of spades cannot<br />
be dealt more than once. However, applying this limit to the generation of diversity would be inappropriate<br />
because each cell that undergoes recombination starts with a full genome. If one cell uses a particular gene<br />
segment, nothing prevents a different cell from using the same one. In real poker, the number of possible<br />
hands is further reduced because the sequence of cards in a hand does not matter. In poker it makes no<br />
difference whether you have the cards “king, ace, ace, ace, ace” or “ace, king, ace, ace, ace.” Both hands<br />
would be counted as “four aces, king high”. However, in the joining of gene segments during somatic<br />
genetic recombination, the sequence does matter. So the closest analogy to the biological condition is a<br />
bottomless deck of cards being dealt to produce hands where the sequence does confer distinction.<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
produced by B-cells are presented on the cell surface and, when appropriately<br />
stimulated, B-cells can transform to become antibody-secreting cells called plasma<br />
cells. Secreted antibodies bind to invading pathogens or infected cells marking the<br />
pathogens or infected cells for destruction by other immune cells (such as killer Tcells).<br />
Generic recombination in T-cells produces genes for TCRs. These TCRs remains<br />
anchored to the T-cell’s plasma membrane and enable the T-cell to recognize antigen.<br />
Thus, the diversity of the immune system consists of the millions of different B-cells,<br />
each possessing the ability to release a different type of antibody, and the millions of<br />
different T-cells, each possessing a different TCR on its surface. Because recombination<br />
can make so many different genes, each TCR gene and each antibody gene is likely to be<br />
unique. This uniqueness manifests itself in the shape, electrical charge, hydrophobicity<br />
and other properties of the antigen binding site of the antibody or TCR. These protein<br />
properties give each antigen-binding site its binding specificity. That is, each different<br />
TCR or antibody will only interact strongly with a small number of specific antigens. The<br />
specificity of binding of antigens to TCRs or antigens to antibodies is an essential feature<br />
of the immune system. The system would not function well if antigen-specific binding<br />
did not exist. If locks could be opened by any key, locks and keys would be obsolete.<br />
Likewise it would be useless to have antibodies or TCRs that bound to everything. To<br />
function properly the immune system must be specific-- able to see dangerous<br />
pathogens as threats and able to ignore everything else.<br />
However, it is important to keep in mind that when we say an immune cell “sees” a<br />
pathogen as threats we attribute properties to an immune cell which it does not have.<br />
Of course, no cell ever truly “sees” anything. They have no eyes and live in permanent<br />
darkness. (Very little light penetrates more than a couple of millimeters into our bodies).<br />
“Seeing” is a useful metaphor for molecular recognition. It is helpful to remember,<br />
however, that it is only a metaphor. It would be more accurate to say an immune cell<br />
possesses the appropriate protein sequence to enable strong interaction between antigen<br />
binding proteins of that cell and the antigens of the pathogen. The strength of this<br />
interaction is the primary basis for the specific recognition that exits in the immune<br />
system. Molecular recognition between molecules that bind to each other can also be<br />
compared to the fit of a key in its corresponding lock. In order for the interaction<br />
between lock and key to be productive, the shape of the key must be the complement of<br />
the shape of the lock. Likewise, in biology, it is very often the case that shape, charge<br />
and other biochemical properties are complementary to the shape and other properties<br />
of the thing bound.<br />
Molecular recognition by a TCR has been well characterized for some antigens. For<br />
example, the coat of the influenza virus includes a protein called hemagglutinin. When<br />
cells are infected with influenza some of the hemagglutinin is broke into smaller pieces<br />
and these pieces are displayed on the surface of certain immune cells, such as<br />
macrophages. One fragment of hemagglutinin has the amino acid sequence IYSTVASSL<br />
(that is, isoleucine-tyrosine-serine-threonine-valine-alanina-serine-serine-leucine). When<br />
this peptide is displayed in the peptide-binding groove of an MHC, those killer T-cells with<br />
just the right TCR will bind tightly to the antigen and will destroy the infected cell.<br />
C. Positive Selection Ensures That Mature T-cells Can Bind The MHC:<br />
The life of a T-cell begins in the bone marrow. See Figure 1. In the marrow,<br />
hematopoietic stem cells divide to produce precursor cells that are released from the<br />
marrow, enter the blood stream, and travel to the thymus. After infiltrating the thymus,<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
precursor cells localize to the outer part of the thymus, called the thymic cortex. Most of<br />
these cells simply die. Indeed, only 5% of thymic precursor cells are successful at<br />
overcoming the many challenges of thymocyte development. There are several ways an<br />
immature thymocyte can fail to make it through the maturation process. One way is if<br />
the thymocyte lacks the ability to effectively bind to a structure called the major<br />
histocompatibility complex, or MHC 2 . The MHC serves as a presenter of small<br />
polypeptides, such as antigens. Typically, T-cells can recognize antigen only when the<br />
antigen is cradled in a crevice of the MHC. It is the combination of MHC and antigen<br />
taken together that trigger recognition in a T-cell. It is the TCR of a T-cell that binds the<br />
MHC-antigen complex. If, in the course of generating its TCR, a thymocyte happens to<br />
be bind MHC very weekly, the thymocyte will soon die. This is called death by neglect.<br />
Approximately 90% of thymocytes undergo death by neglect. These cells were unlucky<br />
when TCR gene segments were being recombined. Instead of producing an effective<br />
TCR these cells produced TCR that do not have enough affinity for MHC.<br />
The alternative to death by neglect is positive selection. If a thymic precursor does<br />
bind to the MHC effectively, the cell receives a signal to survive and does not die. These<br />
surviving cells have been positively selected for their ability to interact effectively with<br />
the MHC. Still, these cells might yet be destroyed by another important process in T-cell<br />
development—negative selection!<br />
D. Self-Tolerance Is Achieved Through Negative Selection:<br />
Perhaps you have seen depictions of police officers-in-training shooting, or holding their<br />
fire as cut-outs of criminals or unarmed people pop into view. This exercise is designed<br />
to sharpen the reflexes of trainees. We want to ensure they are careful enough to avoid<br />
shooting children, surrendering criminals, pregnant mothers, etc., yet decisive enough to<br />
use sufficient force against a real threat. The immune system must perform a similar kind<br />
of discrimination. The immune system must distinguish between the body’s own<br />
antigens, which immunologists call “self” and the antigens of pathogens. When an<br />
organism’s immune system does discriminate properly between pathogens and self it is<br />
said to be self-tolerant. When an organism fails to achieve self-tolerance, the immune<br />
system attacks the body’s own cells. This is the cause of auto-immune disease.<br />
Because the recombining that generates immunologic diversity is somewhat haphazard,<br />
there is no guarantee that the immune system will avoid generating antigen-binding sites<br />
specific for molecules that are part of one’s own body. The immune cells that express<br />
such antigen-binding sites are said to be “self-reactive.” They experience TCR<br />
stimulation in response to the bodies own molecules. Self-reactivity is such a potentially<br />
serious problem that an ingenious mechanism exists to prevent it. Before a person is<br />
even born, the body begins to destroy developing T-cells that exhibit strong binding to<br />
self antigen. This process is called negative selection. It is as if the immune system<br />
made the assumption that, immature thymocytes have a very small chance of<br />
encountering pathogens, but a very good chance of encountering self molecules in the<br />
thymus. If a thymocyte does bind self-molecules at this early developmental stage, TCR<br />
stimulation causes a series of biochemical reactions that ultimately cause the cell to kill<br />
itself. This sort of cellular suicide is called apoptosis. Interestingly, a mature T-cell<br />
responds in an entirely different manner when it binds to antigens. In this case, instead<br />
of killing itself, antigen binding triggers the mature T-cell to rapidly divide, producing<br />
numerous clones of itself. This will be discussed in more depth in section F below.<br />
2 It is more appropriate to apply the term “MHC” to the set of genes that encode the antigen-presenting proteins. In<br />
humans, these genes are referred to as human leukocyte antigen (HLA) genes, although people often use the<br />
abbreviation “MHC” to refer to HLA gene products, as I do in this document. To avoid confusion some use “Mhc” to refer<br />
to the HLA protein molecules and reserve “MHC” for the region of the genome that encodes for this molecule.<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Imagine a police academy where the pool of trainees enters with all sorts of bizarre and<br />
unalterable personalities. Some always shoot at armed robbers and only armed robbers,<br />
some at snipers and only snipers, some at knife-wielding rapists, some at schoolchildren<br />
and some at harmless pedestrians. If we expose these trainees to all the various things<br />
they might encounter, (such as, robbers, snipers, rapists, children and pedestrians) we<br />
can weed out those with an inappropriate specificity. After the homicidal trainees have<br />
been weeded out, the protective police can be sent out to patrol. Likewise, after all selfreactive<br />
immune cells have been destroyed, a person is said to be “self-tolerant.” The<br />
immune system of a self-tolerant person should only attack foreign substances.<br />
However, if, for some reason, the process of weeding out self-reactive T-cells is<br />
incomplete, surviving self-reactive cells may develop into mature cells. Now, when<br />
exposed to antigen (which in this case would be some self molecule) these mature cells<br />
proliferate to produce an immune defense against one’s own body. This is what happens<br />
during certain autoimmune diseases. Likewise, when tissue transplants are performed,<br />
the mature immune system of the recipient is full of mature immune cells that proliferate<br />
when they encounter transplant antigens. Since the transplanted tissue was not around<br />
during immune cell training, the transplant may be attacked as if it were a pathogen.<br />
The transplanted tissue could then be damaged or destroyed and the benefit of<br />
transplantation lost.<br />
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Figure 1<br />
AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Bone Death<br />
by Neglect Thymus<br />
Positive<br />
Selection<br />
Immature<br />
Hematopoietic <strong>Thymocyte</strong>s<br />
Stem Cell<br />
Death by<br />
Negative Selection<br />
Thymic<br />
Precursor Mature<br />
Cells Self-tolerant<br />
T-Cell<br />
Travel to<br />
The Periphery<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
E. TCR-Stimulation in Mature T-cells Results in T-Cell Activation:<br />
If a T-cell survives the weeding-out processes of positive and negative selection, it will<br />
exit the thymus and complete its maturation in the lymphatic system. Most importantly,<br />
it is in lymphatic organs that mature T-cell will encounter antigen and undergo activation.<br />
The lymphatic system is an organ system that consists of lymph nodes, lymphatic vessels<br />
and the spleen. Fluid and cells that exit the blood stream are recirculated back to the<br />
blood by way of the lymphatic system. In addition, lymphatic organs are sites scattered<br />
throughout the body that serve as gathering places for immune cells. In a sense,<br />
lymphatic organs are where immune cells conduct meetings. When T-cells exit the<br />
thymus they are carried to the lymph. The vast majority of T-cells will remain dormant<br />
within the lymph. This is because the antigen they happen to recognize is not being<br />
displayed by any antigen-presenting cells. However, there will be a tiny fraction of the<br />
mature T-cell repertoire that do happen to have the right TCRs to recognize the antigens<br />
being displayed in the lymphatic system. If a T-cell does recognize a presented antigen,<br />
that cell’s TCR will be stimulated and the cell will undergo activation. Upon activation, Tcells<br />
can change into various types of effector cells through a process called<br />
differentiation. For example, they can become cytotoxic T-cells or helper T-cells. In<br />
addition to differentiating, activated T-cells also make copies of themselves—they<br />
proliferate. This ensures that there will be many T-cells in the body that are capable of<br />
recognizing the particular antigen that happens to be present. Cytotoxic T-cell and<br />
helper T-cell are the main effectors of cell-mediated immunity. Helper T-cells help fight<br />
infection by activating cytotoxic T-cells, by activating B-cells, and by stimulating the<br />
humoral response. Cytotoxic T-cells help fight infection by binding to the body’s infected<br />
cells and destroying them. This prevents the infection from spreading to uninfected cells.<br />
Cytotoxic T-cell may also kill cancer cells.<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
Figure 2<br />
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AAI Curriculum Unit: <strong>Understanding</strong> <strong>Immunity</strong> <strong>By</strong> <strong>Tracing</strong> <strong>Thymocyte</strong> <strong>Development</strong><br />
F. TCR Stimulation Produces Entirely Different Responses in Mature T-Cells<br />
Compared to Immature <strong>Thymocyte</strong>s:<br />
Negative selection depends on the fact that TCR-stimulation of immature thymocytes<br />
causes those thymocytes to undergo apoptosis. Yet, the very same stimulation, will,<br />
cause a mature T-cell to survive and even reproduce. Something must have changed<br />
within the immature cell to account for such radical change in the way it responds to TCR<br />
binding. The full details of this change are not yet known. Instead, this question is<br />
being actively investigated, in Dr. Punt’s laboratory, among others. One reasonable<br />
hypothesis is that the molecules that convey signals from the cell surface differ in some<br />
important way in mature verses immature thymocytes. Several such signal-transduction<br />
molecules are being investigated for their role in triggering apoptosis and/or proliferation.<br />
One molecule of special interest is Nur77. Nur77 is a steroid receptor that acts as a<br />
transcription factor—a protein that triggers the transcription of genes. When Nur77 is<br />
over-expressed in an immature thymocyte, the cell undergoes apoptosis. It has also been<br />
shown that expression of Nur77 in transgenic mice results in a sharp increase in the<br />
quantity of several mRNAs. Since Nur77 is a transcription factor, this is exactly what one<br />
would expect. It may be that the proteins encoded by these mRNAs are important in<br />
causing apoptosis.<br />
One way of examining the importance of transcription to apoptosis is to purify the<br />
mRNAs from mature and immature cells after each has had its TCRs stimulated by<br />
binding to antigen-like molecules. If some mRNAs are highly expressed in immature cells<br />
but not in mature cells, these mRNAs may be involved in bringing about apoptosis.<br />
Together with Dr. Punt, and others, I investigated differences in the quantities of various<br />
mRNAs in TCR-stimulated mature T-cells compared with TCR-stimulated immature cells.<br />
Activity III presents some of the data obtained in this investigation. It is intriguing to<br />
consider that changes in the abundance of certain mRNAs might lead to the radically<br />
different responses of T-cells to stimulation at different points in their maturation.<br />
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